Macrocyclic factor xia inhibitors condensed with heterocycles

ABSTRACT

The present invention provides compounds of Formula (Ia): 
     
       
         
         
             
             
         
       
     
     or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein all the variables are as defined herein. These compounds are selective factor XIa inhibitors or dual inhibitors of FXIa and plasma kallikrein. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating thromboembolic and/or inflammatory disorders using the same.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. application Ser. No.15/115,319, filed Jul. 29, 2016, which is the 371 National Stage ofInternational Application No. PCT/US2015/013647, filed Jan. 30, 2015,which claims the priority benefit of U.S. provisional patent applicationNo. 61/933,948, filed on Jan. 31, 2014, the contents of which areincorporated herein in their entirety.

FIELD OF THE INVENTION

The present invention relates generally to novel macrocyclic compounds,and their analogues thereof, which are factor XIa inhibitors or dualinhibitors of factor XIa and plasma kallikrein, compositions containingthem, and methods of using them, for example, for the treatment orprophylaxis of thromboembolic disorders, or for the treatment of retinalvascular permeability associated with diabetic retinopathy and diabeticmacular edema.

BACKGROUND OF THE INVENTION

Thromboembolic diseases remain the leading cause of death in developedcountries despite the availability of anticoagulants such as warfarin(COUMADIN®), heparin, low molecular weight heparins (LMWH), andsynthetic pentasaccharides and antiplatelet agents such as aspirin andclopidogrel (PLAVIX®). The oral anticoagulant warfarin, inhibits thepost-translational maturation of coagulation factors VII, IX, X andprothrombin, and has proven effective in both venous and arterialthrombosis. However, its usage is limited due to its narrow therapeuticindex, slow onset of therapeutic effect, numerous dietary and druginteractions, and a need for monitoring and dose adjustment. Thusdiscovering and developing safe and efficacious oral anticoagulants forthe prevention and treatment of a wide range of thromboembolic disordershas become increasingly important.

One approach is to inhibit thrombin generation by targeting theinhibition of coagulation factor XIa (FXIa). Factor XIa is a plasmaserine protease involved in the regulation of blood coagulation, whichis initiated in vivo by the binding of tissue factor (TF) to factor VII(FVII) to generate factor VIIa (FVIIa). The resulting TF:FVIIa complexactivates factor IX (FIX) and factor X (FX) that leads to the productionof factor Xa (FXa). The generated FXa catalyzes the transformation ofprothrombin into small amounts of thrombin before this pathway is shutdown by tissue factor pathway inhibitor (TFPI). The process ofcoagulation is then further propagated via the feedback activation ofFactors V, VIII and XI by catalytic amounts of thrombin. (Gailani, D. etal., Arterioscler. Thromb. Vasc. Biol., 27:2507-2513 (2007).) Theresulting burst of thrombin converts fibrinogen to fibrin thatpolymerizes to form the structural framework of a blood clot, andactivates platelets, which are a key cellular component of coagulation(Hoffman, M., Blood Reviews, 17:S1-S5 (2003)). Therefore, factor XIaplays a key role in propagating this amplification loop and is thus anattractive target for anti-thrombotic therapy.

An alternative way of initiation of coagulation is operative when bloodis exposed to artificial surfaces. This process is also termed contactactivation. Surface absorption of factor XII leads to a conformationalchange in the factor XII molecule, thereby facilitating activation toproteolytic active factor XII molecules (factor XIIa and factor XIIf).Factor XIIa (or XIIf) has a number of target proteins, including plasmaprekallikrein and factor XI.

Plasma prekallikrein is a zymogen of a trypsin-like serine protease andis present in plasma at 35 to 50 μg/mL. The gene structure is similar tothat of factor XI. Overall, the amino acid sequence of plasma kallikreinhas 58% homology to factor XI. Plasma kallikrein is thought to play arole in a number of inflammatory disorders. The major inhibitor ofplasma kallikrein is the serpin C1 esterase inhibitor. Patients whopresent with a genetic deficiency in C1 esterase inhibitor suffer fromhereditary angioedema (HAE) which results in intermittent swelling offace, hands, throat, gastrointestinal tract and genitals. Blistersformed during acute episodes contain high levels of plasma kallikreinwhich cleaves high molecular weight kininogen liberating bradykininleading to increased vascular permeability. Treatment with a largeprotein plasma kallikrein inhibitor has been shown to effectively treatHAE by preventing the release of bradykinin which causes increasedvascular permeability (Lehmann, “Ecallantide (DX-88), a plasmakallikrein inhibitor for the treatment of hereditary angioedema and theprevention of blood loss in on-pump cardiothoracic surgery”, ExpertOpin. Biol. Ther., 8:1187-1199 (2008)).

The plasma kallikrein-kinin system is abnormally abundant in patientswith advanced diabetic macular edema. It has been recently publishedthat plasma kallikrein contributes to retinal vascular dysfunctions indiabetic rats (Clermont, A. et al., “Plasma kallikrein mediates retinalvascular dysfunction and induces retinal thickening in diabetic rats”,Diabetes, 60:1590-1598 (2011)). Furthermore, administration of theplasma kallikrein inhibitor ASP-440 ameliorated both retinal vascularpermeability and retinal blood flow abnormalities in diabetic rats.Therefore, a plasma kallikrein inhibitor should have utility as atreatment to reduce retinal vascular permeability associated withdiabetic retinopathy and diabetic macular edema. Other complications ofdiabetes such as cerebral hemorrhage, nephropathy, cardiomyopathy andneuropathy, all of which have associations with plasma kallikrein mayalso be considered as targets for a plasma kallikrein inhibitor.

To date, no small molecule synthetic plasma kallikrein inhibitor hasbeen approved for medical use. The large protein plasma kallikreininhibitors present risks of anaphylactic reactions, as has been reportedfor Ecallantide. Thus there remains a need for compounds that inhibitplasma kallikrein, that do not induce anaphylaxis and that are orallyavailable. Furthermore, the molecules in the known art feature a highlypolar and ionizable guanidine or amidine functionality. It is well knownthat such functionalities may be limiting to gut permeability andtherefore to oral availability.

SUMMARY OF THE INVENTION

The present invention provides novel macrocyclic compounds, theiranalogues, including stereoisomers, tautomers, pharmaceuticallyacceptable salts, or solvates thereof, which are useful as selectivefactor XIa inhibitors or dual inhibitors of factor XIa and plasmakallikrein.

The present invention also provides processes and intermediates formaking the compounds of the present invention.

The present invention also provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and at least one of thecompounds of the present invention or stereoisomers, tautomers,pharmaceutically acceptable salts, or solvates thereof.

The compounds of the invention may be used in the treatment and/orprophylaxis of thromboembolic disorders.

The compounds of the invention may be used in the treatment of retinalvascular permeability associated with diabetic retinopathy and diabeticmacular edema.

The compounds of the present invention may be used in therapy.

The compounds of the present invention may be used for the manufactureof a medicament for the treatment and/or prophylaxis of a thromboembolicdisorder.

The compounds of the invention can be used alone, in combination withother compounds of the present invention, or in combination with one ormore, preferably one to two other agent(s).

These and other features of the invention will be set forth in expandedform as the disclosure continues.

DETAILED DESCRIPTION OF THE INVENTION I. Compounds of the Invention

In one aspect, the present invention provides, inter alia, compounds ofFormula (I):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

--- is an optional bond;

ring A is independently selected from

R¹ and R² are independently selected from H, F, C₁₋₄ alkyl, alkoxy, andhydroxyl;

R³, at each occurrence, is independently selected from H, C₁₋₄alkyl,C₁₋₄haloalkyl, —(CH₂)_(n)—OR⁵, —(CH₂)_(n)—C(O)OR⁵, and C₃₋₆ cycloalkyl;

R⁴ is independently selected from H, OH, F, OC₁₋₄ alkyl, C₁₋₄ alkyl, andCN;

R⁵ is independently selected from H and C₁₋₄ alkyl;

R⁶ is independently selected from H, F, Cl, Br, CN, OCH₃, CH₃, C(O)CH₃,CF₃, OCHF₂, NHC(O)C₁₋₄ alkyl, aryl, C₃₋₆ cycloalkyl, and 4-6 memberedheterocycle substituted with R⁹;

R⁷ is independently selected from H and F;

R⁸ is independently selected from H, F, Cl, and OCH₃;

R⁹ is independently selected from H, C₁₋₄ alkyl and halogen; and

n, at each occurrence, is an integer independently selected from 0, 1,and 2.

In another aspect, the present invention provides compounds of Formula(II):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

R¹ and R² are independently selected from H and C₁₋₄ alkyl;

R³ is independently selected from H, C₁₋₄alkyl, C₁₋₄haloalkyl,—(CH₂)_(n)—OR⁵, —(CH₂)_(n)—C(O)OR⁵, and C₃₋₆ cycloalkyl;

R⁵ is independently selected from H and C₁₋₄ alkyl;

R⁶ is independently selected from H, F, CF₃, and triazole substitutedwith R⁹;

R⁷ is independently selected from H and F;

R⁸ is independently selected from H, F, and Cl;

R⁹ is independently selected from H and halogen; and

n, at each occurrence, is an integer independently selected from 0, 1,and 2.

In another aspect, the present invention provides compounds of Formula(II), or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

R¹ and R² are independently selected from H and CH₃;

R³ is independently selected from H, CH₃, CH₂CH₃, —CH₂CHF₂, —CH₂CF₃,—(CH₂)_(n)—OH, —(CH₂)_(n)—C(O)OH, and cyclopropyl;

R⁶ is independently selected from F, CF₃, and

R⁷ is independently selected from H and F;

R⁸ is independently selected from H, F, and Cl;

R⁹ is independently selected from H and Cl; and

n, at each occurrence, is an integer independently selected from 0, 1,and 2.

In another aspect, the present invention provides compounds of Formula(III):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

R¹ and R² are independently selected from H and C₁₋₄ alkyl;

R³ is independently selected from H, —(CH₂)_(n)—C(O)OH;

R⁶ is independently selected from H, F, CF₃, and triazole substitutedwith R⁹;

R⁷ is independently selected from H and F;

R⁸ is independently selected from H, F, and Cl;

R⁹ is independently selected from H and halogen; and

n, at each occurrence, is an integer independently selected from 0, 1,and 2.

In another aspect, the present invention provides compounds of Formula(II), or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

R⁶ is independently selected from F, CF₃ and

R⁷ is independently selected from H and F;

R⁸ is Cl;

R⁹ is independently selected from H and Cl; and

other variables are as defined in Formula (II).

In another aspect, the present invention provides compounds of Formula(II), or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

R⁶ is independently selected from F, CF₃ and

R⁷ is independently selected from H and F;

R⁸ is Cl;

R⁹ is independently selected from H and Cl; and

other variables are as defined in Formula (III).

In another aspect, the present invention provides compounds of Formula(Ia):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

--- is an optional bond;

ring A is independently selected from

R¹ is independently selected from H, F, OH, and C₁₋₄ alkyl;

R² is independently selected from H, F, and OH;

R³ is independently selected from H, C₁₋₄alkyl, C₁₋₄haloalkyl,—(CH₂)_(n)—OR⁵, —(CH₂)_(n)—C(O)OR⁵, C₃₋₆ cycloalkyl optionallysubstituted with halogen, and 5- to 6-membered heteroaryl comprisingcarbon atoms and 1-2 nitrogen atoms and optionally substituted with R¹;provided only one R³ group is present on the ring;

R⁴ is independently selected from H, OH, F, OC₁₋₄ alkyl, C₁₋₄ alkyl, andCN;

R⁵ is independently selected from H and C₁₋₄ alkyl;

R⁶ is independently selected from H, F, Cl, Br, CN, OCH₃, CH₃, C(O)CH₃,CHF₂, CCH₃F₂, CF₃, OCHF₂, NHC(O)C₁₋₄ alkyl, C₃₋₆ cycloalkyl, and5-membered heterocycle substituted with R⁹;

R⁷ is independently selected from H and F;

R⁸ is independently selected from H, F, Cl, and OCH₃;

R⁹ is independently selected from H, cyano, C₁₋₄ alkyl, haloalkyl, andhalogen; and

n, at each occurrence, is an integer selected from 1 and 2.

In another aspect, the present invention provides compounds of Formula(IIa):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

ring A is independently selected from

R¹ is independently selected from H and C₁₋₃alkyl;

R² is independently selected from H and F;

R³ is independently selected from H, C₁₋₃alkyl, C₁₋₃haloalkyl,—(CH₂)_(n)—OR, —(CH₂)_(n)—C(O)OR⁵, and C₃₋₄ cycloalkyl optionallysubstituted with halogen;

R⁴ is independently selected from H and F;

R⁵ is independently selected from H and C₁₋₄ alkyl;

R⁶ is independently selected from H, F, Cl, Br, CN, CF₃, C(O)CH₃, CHF₂,CCH₃F₂, CF₃, OCHF₂,

R⁷ is independently selected from H and F;

R⁸ is independently selected from H, F, Cl, and OCH₃;

R⁹ is independently selected from H, CHF₂, and CF₃;

R^(9′) is independently selected from H, F, Cl, CN, CHF₂, and CF₃; and

n, at each occurrence, is an integer selected from 1 and 2.

In another aspect, the present invention provides compounds of Formula(IIa) or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

R¹ is independently selected from H, CH₃, and CH(CH₃)₂;

R² is independently selected from H and F;

R³ is independently selected from H, CH₃, CD₃, CH₂CH₃, —CHF₂, —CH₂CHF₂,—CH₂CF₃, —CH₂CH₂OH, CH₂CH₂OC(CH₃)₃, —CH₂C(O)OH, cyclopropyl optionallysubstituted with F, and cyclobutyl;

R⁶ is independently selected from H, F, Cl, Br, CN, CF₃, C(O)CH₃, CHF₂,CCH₃F₂, CF₃, OCHF₂,

R⁷ is independently selected from H and F;

R⁸ is independently selected from H, F, Cl, and OCH₃;

R⁹ is independently selected from H, CHF₂, and CF₃; and

R^(9′) is independently selected from H, F, Cl, CN, CHF₂, and CF₃.

In another aspect, the present invention provides compounds of Formula(IIIa):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

ring A is independently selected from

R¹ is independently selected from H, CH₃, and CH(CH₃)₂;

R² is independently selected from H and F;

R³ is independently selected from H, CH₂C(═O)OH, CH₂C(═O)OCH₂CH₃,

R⁴ is independently selected from H and F;

R⁶ is independently selected from H, F, Cl, Br, CN, CF₃, C(O)CH₃, CHF₂,CCH₃F₂, CF₃, OCHF₂,

R⁷ is independently selected from H and F;

R⁸ is independently selected from H, F, Cl, and OCH₃;

R⁹ is independently selected from H, CHF₂, and CF₃; and

R^(9′) is independently selected from H, F, Cl, CN, CHF₂, and CF₃.

In another aspect, the present invention provides compounds of Formula(Ia), or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

R³ is independently selected from H, CH₃, CD₃, CH₂CH₃, CHF₂, CH₂CHF₂,CH₂CF₃, CH₂CH₂OH, CH₂CH₂OC(CH₃)₃, CH₂C(O)OH, CH₂C(═O)OH,CH₂C(═O)OCH₂CH₃, cyclopropyl optionally substituted with F, andcyclobutyl,

R⁶ is independently selected from H, F, Cl, Br, CN, CF₃, C(O)CH₃, CHF₂,CCH₃F₂, CF₃, OCHF₂,

R⁷ is independently selected from H and F;

R⁸ is Cl;

R⁹ is independently selected from H, CHF₂, and CF₃; and

R^(9′) is independently selected from H, F, Cl, CN, CHF₂, and CF₃; and

other variables are as defined in Formula (Ia).

In another aspect, the present invention provides compounds of Formula(IV):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

ring A is independently selected from

R¹ is independently selected from H and C₁₋₃alkyl;

R² is independently selected from H and F;

R³ is independently selected from H, CD₃, CHF₂, and CH₃;

R⁴ is independently selected from H and halogen;

R⁷ is independently selected from H and F;

R⁸ is independently selected from H, F, Cl, and OCH₃; and

R⁹ is independently selected from H, F, Cl, CN, and CF₃.

In another aspect, the present invention provides compounds of Formula(V):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

ring A is independently selected from

R¹ is independently selected from H and C₁₋₃alkyl;

R² is independently selected from H and F;

R³ is independently selected from H, CD₃, CHF₂, and CH₃;

R⁴ is independently selected from H and halogen;

R⁶ is independently selected from H, F, Cl, Br, CN, CF₃, C(O)CH₃, CHF₂,CCH₃F₂, CF₃, OCHF₂,

R⁷ is independently selected from H and F;

R⁸ is independently selected from H, F, Cl, and OCH₃;

R⁹ is independently selected from H, CHF₂, and CF₃; and

R^(9′) is independently selected from H, F, Cl, CN, CHF₂, and CF₃.

In another embodiment, R¹ is independently selected from the groupconsisting of H, OH, and C₁₋₄ alkyl; R² is, independently at eachoccurrence, selected from the group consisting of H and F.

In another embodiment, R¹ is independently selected from the groupconsisting of H and methyl, ethyl, and isopropyl; R² is H or F.

In another aspect, the present invention provides a compound selectedfrom any subset list of compounds exemplified in the presentapplication.

In another embodiment, the present invention provides a compoundselected from

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof.

II. Other Embodiments of the Invention

In another embodiment, the present invention provides a compositioncomprising at least one of the compounds of the present invention or astereoisomer, a tautomer, a pharmaceutically acceptable salt, or asolvate thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atleast one of the compounds of the present invention or a stereoisomer, atautomer, a pharmaceutically acceptable salt, or a solvate, thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition, comprising: a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof.

In another embodiment, the present invention provides a process formaking a compound of the present invention.

In another embodiment, the present invention provides an intermediatefor making a compound of the present invention.

In another embodiment, the present invention provides a pharmaceuticalcomposition further comprising additional therapeutic agent(s). In apreferred embodiment, the present invention provides pharmaceuticalcomposition, wherein the additional therapeutic agent(s) are ananti-platelet agent or a combination thereof. Preferably, theanti-platelet agent(s) are clopidogrel and/or aspirin, or a combinationthereof.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of a thromboembolic disorder comprisingadministering to a patient in need of such treatment and/or prophylaxisa therapeutically effective amount of at least one of the compounds ofthe present invention or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof.

In another embodiment, the present invention provides a compound of thepresent invention or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof, for use in therapy.

In another embodiment, the present invention provides a compound of thepresent invention or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof, for use in therapy for thetreatment and/or prophylaxis of a thromboembolic disorder.

In another embodiment, the present invention also provides the use of acompound of the present invention or a stereoisomer, a tautomer, apharmaceutically acceptable salt, or a solvate thereof, for themanufacture of a medicament for the treatment and/or prophylaxis of athromboembolic disorder.

In another embodiment, the present invention provides a method fortreatment and/or prophylaxis of a thromboembolic disorder, comprising:administering to a patient in need thereof a therapeutically effectiveamount of a first and second therapeutic agent, wherein the firsttherapeutic agent is a compound of the present invention or astereoisomer, a tautomer, a pharmaceutically acceptable salt, or asolvate thereof, and the second therapeutic agent is at least one agentselected from a factor Xa inhibitor such as apixaban, rivaroxaban,betrixaban, edoxaban, an anticoagulant agent, an anti-platelet agent, athrombin inhibiting agent such as dabigatran, a thrombolytic agent, anda fibrinolytic agent. Preferably, the second therapeutic agent is atleast one agent selected from warfarin, unfractionated heparin, lowmolecular weight heparin, synthetic pentasaccharide, hirudin,argatroban, aspirin, ibuprofen, naproxen, sulindac, indomethacin,mefenamate, droxicam, diclofenac, sulfinpyrazone, piroxicam,ticlopidine, clopidogrel, tirofiban, eptifibatide, abciximab,melagatran, desulfatohirudin, tissue plasminogen activator, modifiedtissue plasminogen activator, anistreplase, urokinase, andstreptokinase. Preferably, the second therapeutic agent is at least oneanti-platelet agent. Preferably, the anti-platelet agent(s) areclopidogrel and/or aspirin, or a combination thereof.

The thromboembolic disorder includes arterial cardiovascularthromboembolic disorders, venous cardiovascular thromboembolicdisorders, arterial cerebrovascular thromboembolic disorders, and venouscerebrovascular thromboembolic disorders. Examples of the thromboembolicdisorder include, but are not limited to, unstable angina, an acutecoronary syndrome, atrial fibrillation, first myocardial infarction,recurrent myocardial infarction, ischemic sudden death, transientischemic attack, stroke, atherosclerosis, peripheral occlusive arterialdisease, venous thrombosis, deep vein thrombosis, thrombophlebitis,arterial embolism, coronary arterial thrombosis, cerebral arterialthrombosis, cerebral embolism, kidney embolism, pulmonary embolism, andthrombosis resulting from medical implants, devices, or procedures inwhich blood is exposed to an artificial surface that promotesthrombosis.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of an inflammatory disorder comprising:administering to a patient in need of such treatment and/or prophylaxisa therapeutically effective amount of at least one of the compounds ofthe present invention or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof. Examples of the inflammatorydisorder include, but are not limited to, sepsis, acute respiratorydistress syndrome, and systemic inflammatory response syndrome.

In another embodiment, the present invention provides a method for theprophylaxis of a disease or condition in which plasma kallikreinactivity is implicated comprising administering to a patient in need ofsuch treatment and/or prophylaxis a therapeutically effective amount ofat least one of the compounds of the present invention or astereoisomer, a tautomer, a pharmaceutically acceptable salt, or asolvate thereof.

The disease or condition in which plasma kallikrein activity isimplicated includes, but not limited to, impaired visual acuity,diabetic retinopathy, diabetic macular edema, hereditary angioedema,diabetes, pancreatitis, nephropathy, cardio myopathy, neuropathy,inflammatory bowel disease, arthritis, inflammation, septic shock,hypotension, cancer, adult respiratory distress syndrome, disseminatedintravascular coagulation, and cardiopulmonary bypass surgery.

In another embodiment, the present invention provides a combinedpreparation of a compound of the present invention and additionaltherapeutic agent(s) for simultaneous, separate or sequential use intherapy.

In another embodiment, the present invention provides a combinedpreparation of a compound of the present invention and additionaltherapeutic agent(s) for simultaneous, separate or sequential use intreatment and/or prophylaxis of a thromboembolic disorder.

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. Thisinvention encompasses all combinations of preferred aspects of theinvention noted herein. It is understood that any and all embodiments ofthe present invention may be taken in conjunction with any otherembodiment or embodiments to describe additional embodiments. It is alsoto be understood that each individual element of the embodiments is itsown independent embodiment. Furthermore, any element of an embodiment ismeant to be combined with any and all other elements from any embodimentto describe an additional embodiment.

III. Chemistry

Throughout the specification and the appended claims, a given chemicalformula or name shall encompass all stereo and optical isomers andracemates thereof where such isomers exist. Unless otherwise indicated,all chiral (enantiomeric and diastereomeric) and racemic forms arewithin the scope of the invention. Many geometric isomers of C═C doublebonds, C═N double bonds, ring systems, and the like can also be presentin the compounds, and all such stable isomers are contemplated in thepresent invention. Cis- and trans- (or E- and Z-) geometric isomers ofthe compounds of the present invention are described and may be isolatedas a mixture of isomers or as separated isomeric forms. The presentcompounds can be isolated in optically active or racemic forms.Optically active forms may be prepared by resolution of racemic forms orby synthesis from optically active starting materials. All processesused to prepare compounds of the present invention and intermediatesmade therein are considered to be part of the present invention. Whenenantiomeric or diastereomeric products are prepared, they may beseparated by conventional methods, for example, by chromatography orfractional crystallization. Depending on the process conditions the endproducts of the present invention are obtained either in free (neutral)or salt form. Both the free form and the salts of these end products arewithin the scope of the invention. If so desired, one form of a compoundmay be converted into another form. A free base or acid may be convertedinto a salt; a salt may be converted into the free compound or anothersalt; a mixture of isomeric compounds of the present invention may beseparated into the individual isomers. Compounds of the presentinvention, free form and salts thereof, may exist in multiple tautomericforms, in which hydrogen atoms are transposed to other parts of themolecules and the chemical bonds between the atoms of the molecules areconsequently rearranged. It should be understood that all tautomericforms, insofar as they may exist, are included within the invention.

The term “stereoisomer” refers to isomers of identical constitution thatdiffer in the arrangement of their atoms in space. Enantiomers anddiastereomers are examples of stereoisomers. The term “enantiomer”refers to one of a pair of molecular species that are mirror images ofeach other and are not superimposable. The term “diastereomer” refers tostereoisomers that are not mirror images. The term “racemate” or“racemic mixture” refers to a composition composed of equimolarquantities of two enantiomeric species, wherein the composition isdevoid of optical activity.

The symbols “R” and “S” represent the configuration of substituentsaround a chiral carbon atom(s). The isomeric descriptors “R” and “S” areused as described herein for indicating atom configuration(s) relativeto a core molecule and are intended to be used as defined in theliterature (IUPAC Recommendations 1996, Pure and Applied Chemistry,68:2193-2222 (1996)).

The term “chiral” refers to the structural characteristic of a moleculethat makes it impossible to superimpose it on its mirror image. The term“homochiral” refers to a state of enantiomeric purity. The term “opticalactivity” refers to the degree to which a homochiral molecule ornonracemic mixture of chiral molecules rotates a plane of polarizedlight.

As used herein, the term “alkyl” or “alkylene” is intended to includeboth branched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms. For example, “C₁ to C₁₀alkyl” or “C₁₋₁₀ alkyl” (or alkylene), is intended to include C₁, C₂,C₃, C₄, C₅, C₆, C₇, C₈, C₉, and C₁₀ alkyl groups. Additionally, forexample, “C₁ to C₆ alkyl” or “C₁-C₆ alkyl” denotes alkyl having 1 to 6carbon atoms.

Alkyl group can be unsubstituted or substituted with at least onehydrogen being replaced by another chemical group. Example alkyl groupsinclude, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g.,n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), andpentyl (e.g., n-pentyl, isopentyl, neopentyl). When “C₀ alkyl” or “C₀alkylene” is used, it is intended to denote a direct bond. “Alkyl” alsoincludes deuteroalkyl such as CD₃.

“Alkenyl” or “alkenylene” is intended to include hydrocarbon chains ofeither straight or branched configuration having one or more, preferablyone to three, carbon-carbon double bonds that may occur in any stablepoint along the chain. For example, “C₂ to C₆ alkenyl” or “C₂₋₆ alkenyl”(or alkenylene), is intended to include C₂, C₃, C₄, C₅, and C₆ alkenylgroups; such as ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

“Alkynyl” or “alkynylene” is intended to include hydrocarbon chains ofeither straight or branched configuration having one or more, preferablyone to three, carbon-carbon triple bonds that may occur in any stablepoint along the chain. For example, “C₂ to C₆ alkynyl” or “C₂₋₆ alkynyl”(or alkynylene), is intended to include C₂, C₃, C₄, C₅, and C₆ alkynylgroups; such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

The term “alkoxy” or “alkyloxy” refers to an —O-alkyl group. “C₁ to C₆alkoxy” or “C₁₋₆ alkoxy” (or alkyloxy), is intended to include C₁, C₂,C₃, C₄, C₅, and C₆ alkoxy groups. Example alkoxy groups include, but arenot limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy andisopropoxy), and t-butoxy. Alkoxy also includes deuteroalkyoxy such asOCD₃. Similarly, “alkylthio” or “thioalkoxy” represents an alkyl groupas defined above with the indicated number of carbon atoms attachedthrough a sulphur bridge; for example methyl-S— and ethyl-S—.

“Halo” or “halogen” includes fluoro, chloro, bromo, and iodo.“Haloalkyl” is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms, substituted with 1 or more halogens. Examples of haloalkylinclude, but are not limited to, fluoromethyl, difluoromethyl,trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl,2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examplesof haloalkyl also include “fluoroalkyl” that is intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms, substituted with 1 or morefluorine atoms.

The term “carbonyl”, as used herein, refers to —C(O)—.

The term “cyano”, as used herein, refers to —CN.

The term “cycloalkylamino”, as used herein, refers to —NHR wherein R isa cycloalkyl group.

The term “haloalkyl”, as used herein, refers to an alkyl groupsubstituted by one, two, three, or four halogen atoms.

The term “carbonyl” refers to C(═O).

The term “carboxy” refers to C(═O)OH.

The term “haloalkylcarbonyl”, as used herein, refers to a haloalkylgroup attached to the parent molecular moiety through a carbonyl group.

The term “hydroxy” or “hydroxyl” refers to OH.

The term “cycloalkyl” refers to cyclized alkyl groups, including mono-,bi- or poly-cyclic ring systems. “C₃ to C₇ cycloalkyl” or “C₃₋₇cycloalkyl” is intended to include C₃, C₄, C₅, C₆, and C₇ cycloalkylgroups. Example cycloalkyl groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl.Branched cycloalkyl groups such as 1-methylcyclopropyl and2-methylcyclopropyl are included in the definition of “cycloalkyl”.

As used herein, “carbocycle” or “carbocyclic residue” is intended tomean any stable 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclic or bicyclicor 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered bicyclic or tricyclichydrocarbon ring, any of which may be saturated, partially unsaturated,unsaturated or aromatic. Examples of such carbocycles include, but arenot limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl,cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl,adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl,[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane(decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl,adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin). As shownabove, bridged rings are also included in the definition of carbocycle(e.g., [2.2.2]bicyclooctane). Preferred carbocycles, unless otherwisespecified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,and indanyl. When the term “carbocycle” is used, it is intended toinclude “aryl”. A bridged ring occurs when one or more carbon atoms linktwo non-adjacent carbon atoms. Preferred bridges are one or two carbonatoms. It is noted that a bridge always converts a monocyclic ring intoa tricyclic ring. When a ring is bridged, the substituents recited forthe ring may also be present on the bridge.

As used herein, the term “bicyclic carbocycle” or “bicyclic carbocyclicgroup” is intended to mean a stable 9- or 10-membered carbocyclic ringsystem that contains two fused rings and consists of carbon atoms. Ofthe two fused rings, one ring is a benzo ring fused to a second ring;and the second ring is a 5- or 6-membered carbon ring which issaturated, partially unsaturated, or unsaturated. The bicycliccarbocyclic group may be attached to its pendant group at any carbonatom which results in a stable structure. The bicyclic carbocyclic groupdescribed herein may be substituted on any carbon if the resultingcompound is stable. Examples of a bicyclic carbocyclic group are, butnot limited to, naphthyl, 1,2-dihydronaphthyl,1,2,3,4-tetrahydronaphthyl, and indanyl.

“Aryl” groups refer to monocyclic or polycyclic aromatic hydrocarbons,including, for example, phenyl, naphthyl, and phenanthranyl. Arylmoieties are well known and described, for example, in Lewis, R. J.,ed., Hawley's Condensed Chemical Dictionary, 13th Edition, John Wiley &Sons, Inc., New York (1997). “C₆ or C₁₀ aryl” or “C₆₋₁₀ aryl” refers tophenyl and naphthyl. Unless otherwise specified, “aryl”, “C₆ or C₁₀aryl” or “C₆₋₁₀ aryl” or “aromatic residue” may be unsubstituted orsubstituted with 1 to 5 groups, preferably 1 to 3 groups, OH, OCH₃, Cl,F, Br, I, CN, NO₂, NH₂, N(CH₃)H, N(CH₃)₂, CF₃, OCF₃, C(═O)CH₃, SCH₃,S(═O)CH₃, S(═O)₂CH₃, CH₃, CH₂CH₃, CO₂H, and CO₂CH₃.

The term “benzyl”, as used herein, refers to a methyl group on which oneof the hydrogen atoms is replaced by a phenyl group, wherein said phenylgroup may optionally be substituted with 1 to 5 groups, preferably 1 to3 groups, OH, OCH₃, Cl, F, Br, I, CN, NO₂, NH₂, N(CH₃)H, N(CH₃)₂, CF₃,OCF₃, C(═O)CH₃, SCH₃, S(═O)CH₃, S(═O)₂CH₃, CH₃, CH₂CH₃, CO₂H, andCO₂CH₃.

As used herein, the term “heterocycle” or “heterocyclic ring” isintended to mean a stable 3-, 4-, 5-, 6-, or 7-membered monocyclic orbicyclic or 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered polycyclicheterocyclic ring that is saturated, partially unsaturated, or fullyunsaturated, and that contains carbon atoms and 1, 2, 3 or 4 heteroatomsindependently selected from the group consisting of N, O and S; andincluding any polycyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring. The nitrogen and sulfurheteroatoms may optionally be oxidized (i.e., N→O and S(O)_(p), whereinp is 0, 1 or 2). The nitrogen atom may be substituted or unsubstituted(i.e., N or NR wherein R is H or another substituent, if defined). Theheterocyclic ring may be attached to its pendant group at any heteroatomor carbon atom that results in a stable structure. The heterocyclicrings described herein may be substituted on carbon or on a nitrogenatom if the resulting compound is stable. A nitrogen in the heterocyclemay optionally be quaternized. It is preferred that when the totalnumber of S and O atoms in the heterocycle exceeds 1, then theseheteroatoms are not adjacent to one another. It is preferred that thetotal number of S and O atoms in the heterocycle is not more than 1.When the term “heterocycle” is used, it is intended to includeheteroaryl.

Examples of heterocycles include, but are not limited to, acridinyl,azetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, imidazolopyridinyl, indolenyl,indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl,methylenedioxyphenyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolopyridinyl, oxazolidinylperimidinyl, oxindolyl,pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl,pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl,pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl,pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl,2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl,4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thiazolopyridinyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Alsoincluded are fused ring and spiro compounds containing, for example, theabove heterocycles.

Examples of 5- to 10-membered heterocycles include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl,tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl,oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl,triazinyl, triazolyl, benzimidazolyl, 1H-indazolyl, benzofuranyl,benzothiofuranyl, benztetrazolyl, benzotriazolyl, benzisoxazolyl,benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl,benzisothiazolyl, isatinoyl, isoquinolinyl, octahydroisoquinolinyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, isoxazolopyridinyl,quinazolinyl, quinolinyl, isothiazolopyridinyl, thiazolopyridinyl,oxazolopyridinyl, imidazolopyridinyl, and pyrazolopyridinyl.

Examples of 5- to 6-membered heterocycles include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl,tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl,oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl,triazinyl, and triazolyl. Also included are fused ring and spirocompounds containing, for example, the above heterocycles.

As used herein, the term “bicyclic heterocycle” or “bicyclicheterocyclic group” is intended to mean a stable 9- or 10-memberedheterocyclic ring system which contains two fused rings and consists ofcarbon atoms and 1, 2, 3, or 4 heteroatoms independently selected fromthe group consisting of N, O and S. Of the two fused rings, one ring isa 5- or 6-membered monocyclic aromatic ring comprising a 5-memberedheteroaryl ring, a 6-membered heteroaryl ring or a benzo ring, eachfused to a second ring. The second ring is a 5- or 6-membered monocyclicring which is saturated, partially unsaturated, or unsaturated, andcomprises a 5-membered heterocycle, a 6-membered heterocycle or acarbocycle (provided the first ring is not benzo when the second ring isa carbocycle).

The bicyclic heterocyclic group may be attached to its pendant group atany heteroatom or carbon atom which results in a stable structure. Thebicyclic heterocyclic group described herein may be substituted oncarbon or on a nitrogen atom if the resulting compound is stable. It ispreferred that when the total number of S and O atoms in the heterocycleexceeds 1, then these heteroatoms are not adjacent to one another. It ispreferred that the total number of S and O atoms in the heterocycle isnot more than 1.

Examples of a bicyclic heterocyclic group are, but not limited to,quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl,isoindolyl, indolinyl, 1H-indazolyl, benzimidazolyl,1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,5,6,7,8-tetrahydro-quinolinyl, 2,3-dihydro-benzofuranyl, chromanyl,1,2,3,4-tetrahydro-quinoxalinyl, and 1,2,3,4-tetrahydro-quinazolinyl.

As used herein, the term “aromatic heterocyclic group” or “heteroaryl”is intended to mean stable monocyclic and polycyclic aromatichydrocarbons that include at least one heteroatom ring member such assulfur, oxygen, or nitrogen. Heteroaryl groups include, withoutlimitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl,pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl,pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl,isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl,benzodioxolanyl, and benzodioxane. Heteroaryl groups are substituted orunsubstituted. The nitrogen atom is substituted or unsubstituted (i.e.,N or NR wherein R is H or another substituent, if defined). The nitrogenand sulfur heteroatoms may optionally be oxidized (i.e., N→O andS(O)_(p), wherein p is 0, 1 or 2).

Bridged rings are also included in the definition of heterocycle. Abridged ring occurs when one or more atoms (i.e., C, O, N, or S) linktwo non-adjacent carbon or nitrogen atoms. Examples of bridged ringsinclude, but are not limited to, one carbon atom, two carbon atoms, onenitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. It isnoted that a bridge always converts a monocyclic ring into a tricyclicring. When a ring is bridged, the substituents recited for the ring mayalso be present on the bridge.

The term “counterion” is used to represent a negatively charged speciessuch as chloride, bromide, hydroxide, acetate, and sulfate.

When a dotted ring is used within a ring structure, this indicates thatthe ring structure may be saturated, partially saturated or unsaturated.

As referred to herein, the term “substituted” means that at least onehydrogen atom is replaced with a non-hydrogen group, provided thatnormal valencies are maintained and that the substitution results in astable compound. When a substituent is keto (i.e., ═O), then 2 hydrogenson the atom are replaced. Keto substituents are not present on aromaticmoieties. When a ring system (e.g., carbocyclic or heterocyclic) is saidto be substituted with a carbonyl group or a double bond, it is intendedthat the carbonyl group or double bond be part (i.e., within) of thering. Ring double bonds, as used herein, are double bonds that areformed between two adjacent ring atoms (e.g., C═C, C═N, or N═N).

In cases wherein there are nitrogen atoms (e.g., amines) on compounds ofthe present invention, these may be converted to N-oxides by treatmentwith an oxidizing agent (e.g., mCPBA and/or hydrogen peroxides) toafford other compounds of this invention. Thus, shown and claimednitrogen atoms are considered to cover both the shown nitrogen and itsN-oxide (N→O) derivative.

When any variable occurs more than one time in any constituent orformula for a compound, its definition at each occurrence is independentof its definition at every other occurrence. Thus, for example, if agroup is shown to be substituted with 0-3 R groups, then said group mayoptionally be substituted with up to three R groups, and at eachoccurrence R is selected independently from the definition of R. Also,combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom in whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms that are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, and/or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic groups such as amines; and alkali or organic saltsof acidic groups such as carboxylic acids. The pharmaceuticallyacceptable salts include the conventional non-toxic salts or thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. For example, suchconventional non-toxic salts include those derived from inorganic acidssuch as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, andnitric; and the salts prepared from organic acids such as acetic,propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, andisethionic.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 18th Edition, Mack Publishing Company, Easton,Pa. (1990), the disclosure of which is hereby incorporated by reference.

In addition, compounds of formula I may have prodrug forms. Any compoundthat will be converted in vivo to provide the bioactive agent (i.e., acompound of formula I) is a prodrug within the scope and spirit of theinvention. Various forms of prodrugs are well known in the art. Forexamples of such prodrug derivatives, see:

-   a) Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985), and    Widder, K. et al., eds., Methods in Enzymology, 112:309-396,    Academic Press (1985);-   b) Bundgaard, H., Chapter 5: “Design and Application of Prodrugs”, A    Textbook of Drug Design and Development, pp. 113-191,    Krosgaard-Larsen, P. et al., eds., Harwood Academic Publishers    (1991);-   c) Bundgaard, H., Adv. Drug Deliv. Rev., 8:1-38 (1992);-   d) Bundgaard, H. et al., J. Pharm. Sci., 77:285 (1988); and-   e) Kakeya, N. et al., Chem. Pharm. Bull., 32:692 (1984).

Compounds containing a carboxy group can form physiologicallyhydrolyzable esters that serve as prodrugs by being hydrolyzed in thebody to yield formula I compounds per se. Such prodrugs are preferablyadministered orally since hydrolysis in many instances occursprincipally under the influence of the digestive enzymes. Parenteraladministration may be used where the ester per se is active, or in thoseinstances where hydrolysis occurs in the blood. Examples ofphysiologically hydrolyzable esters of compounds of formula I includeC₁₋₆alkyl, C₁₋₆alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl,methoxymethyl, C₁₋₆ alkanoyloxy-C₁₋₆alkyl (e.g., acetoxymethyl,pivaloyloxymethyl or propionyloxymethyl),C₁₋₆alkoxycarbonyloxy-C₁₋₆alkyl (e.g., methoxycarbonyl-oxymethyl orethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl), and other well knownphysiologically hydrolyzable esters used, for example, in the penicillinand cephalosporin arts. Such esters may be prepared by conventionaltechniques known in the art.

Preparation of prodrugs is well known in the art and described in, forexample, King, F. D., ed., Medicinal Chemistry: Principles and Practice,The Royal Society of Chemistry, Cambridge, UK (1994); Testa, B. et al.,Hydrolysis in Drug and Prodrug Metabolism. Chemistry, Biochemistry andEnzymology, VCHA and Wiley-VCH, Zurich, Switzerland (2003); Wermuth, C.G., ed., The Practice of Medicinal Chemistry, Academic Press, San Diego,Calif. (1999).

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include deuteriumand tritium. Deuterium has one proton and one neutron in its nucleus andthat has twice the mass of ordinary hydrogen. Deuterium can berepresented by symbols such as “²H” or “D”. The term “deuterated”herein, by itself or used to modify a compound or group, refers toreplacement of one or more hydrogen atom(s), which is attached tocarbon(s), with a deuterium atom. Isotopes of carbon include ¹³C and¹⁴C.

Isotopically-labeled compounds of the invention can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described herein, using an appropriateisotopically-labeled reagent in place of the non-labeled reagentotherwise employed. Such compounds have a variety of potential uses,e.g., as standards and reagents in determining the ability of apotential pharmaceutical compound to bind to target proteins orreceptors, or for imaging compounds of this invention bound tobiological receptors in vivo or in vitro.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. It is preferred that compounds of thepresent invention do not contain a N-halo, S(O)₂H, or S(O)H group.

The term “solvate” means a physical association of a compound of thisinvention with one or more solvent molecules, whether organic orinorganic. This physical association includes hydrogen bonding. Incertain instances the solvate will be capable of isolation, for examplewhen one or more solvent molecules are incorporated in the crystallattice of the crystalline solid. The solvent molecules in the solvatemay be present in a regular arrangement and/or a non-orderedarrangement. The solvate may comprise either a stoichiometric ornonstoichiometric amount of the solvent molecules. “Solvate” encompassesboth solution-phase and isolable solvates. Exemplary solvates include,but are not limited to, hydrates, ethanolates, methanolates, andisopropanolates. Methods of solvation are generally known in the art.

Abbreviations as used herein, are defined as follows: “1×” for once,“2×” for twice, “3×” for thrice, “° C.” for degrees Celsius, “eq” forequivalent or equivalents, “g” for gram or grams, “mg” for milligram ormilligrams, “L” for liter or liters, “mL” for milliliter or milliliters,“μL” for microliter or microliters, “N” for normal, “M” for molar,“mmol” for millimole or millimoles, “min” for minute or minutes, “h” forhour or hours, “rt” for room temperature, “RT” for retention time, “RBF”for round bottom flask, “atm” for atmosphere, “psi” for pounds persquare inch, “conc.” for concentrate, “RCM” for ring-closing metathesis,“sat” or “sat'd” for saturated, “SFC” for supercritical fluidchromatography “MW” for molecular weight, “mp” for melting point, “ee”for enantiomeric excess, “MS” or “Mass Spec” for mass spectrometry,“ESI” for electrospray ionization mass spectroscopy, “HR” for highresolution, “HRMS” for high resolution mass spectrometry, “LCMS” forliquid chromatography mass spectrometry, “HPLC” for high pressure liquidchromatography, “RP HPLC” for reverse phase HPLC, “TLC” or “tlc” forthin layer chromatography, “NMR” for nuclear magnetic resonancespectroscopy, “nOe” for nuclear Overhauser effect spectroscopy, “¹H” forproton, “δ” for delta, “s” for singlet, “d” for doublet, “t” fortriplet, “q” for quartet, “m” for multiplet, “br” for broad, “Hz” forhertz, and “α”, “β”, “R”, “S”, “E”, and “Z” are stereochemicaldesignations familiar to one skilled in the art.

-   Me methyl-   Et ethyl-   Pr propyl-   i-Pr isopropyl-   Bu butyl-   i-Bu isobutyl-   t-Bu tert-butyl-   Ph phenyl-   Bn benzyl-   Boc or BOC tert-butyloxycarbonyl-   Boc₂O di-tert-butyl dicarbonate-   AcOH or HOAc acetic acid-   AlCl₃ aluminum chloride-   AIBN azobisisobutyronitrile-   BBr₃ boron tribromide-   aqueous aq-   BCl₃ boron trichloride-   BEMP    2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine-   BOP reagent benzotriazol-1-yloxytris(dimethylamino)phosphonium    hexafluorophosphate-   Burgess reagent 1-methoxy-N-triethylammoniosulfonyl-methanimidate-   Cbz carbobenzyloxy-   DCM or CH₂Cl₂ dichloromethane-   CH₃CN or ACN acetonitrile-   CDCl₃ deutero-chloroform-   CHCl₃ chloroform-   mCPBA or m-CPBA meta-chloroperbenzoic acid-   Cs₂CO₃ cesium carbonate-   Cu(OAc)₂ copper (II) acetate-   Cy₂NMe N-cyclohexyl-N-methylcyclohexanamine-   CuI copper(I) iodide-   CuSO₄ copper(II) sulfate-   DBU 1,8-diazabicyclo[5.4.0]undec-7-ene-   DCE 1,2 dichloroethane-   DEA diethylamine-   Dess-Martin    1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-beniziodoxol-3-(1H)-one-   DIC or DIPCDI diisopropylcarbodiimide-   DIEA, DIPEA or Hunig's base diisopropylethylamine-   DMAP 4-dimethylaminopyridine-   DME 1,2-dimethoxyethane-   DMF dimethyl formamide-   DMSO dimethyl sulfoxide-   cDNA complimentary DNA-   Dppp (R)-(+)-1,2-bis(diphenylphosphino)propane-   DuPhos (+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene-   EDC N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide-   EDCI N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride-   EDTA ethylenediaminetetraacetic acid-   (S,S)-EtDuPhosRh(I)    (+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene(1,5-cyclooctadiene)rhodium(I)    trifluoromethanesulfonate-   Et₃N or TEA triethylamine-   EtOAc ethyl acetate-   Et₂O diethyl ether-   EtOH ethanol-   GMF glass microfiber filter-   Grubbs II    (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro    (phenylmethylene)(triycyclohexylphosphine)ruthenium-   HCl hydrochloric acid-   HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HEPES 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid-   Hex hexane-   HOBt or HOBT 1-hydroxybenzotriazole-   H₂O₂ hydrogen peroxide-   H₂SO₄ sulfuric acid-   IBX 2-iodoxybenzoic acid-   InCl₃ Indium(III) chloride-   Jones reagent CrO₃ in aqueous H₂SO₄, 2 M-   K₂CO₃ potassium carbonate-   K₂HPO₄ potassium phosphate dibasic-   K₃PO₄ potassium phosphate tribasic-   KOAc potassium acetate-   K₃PO₄ potassium phosphate-   LAH lithium aluminum hydride-   LG leaving group-   LiOH lithium hydroxide-   MeOH methanol-   MgSO₄ magnesium sulfate-   MsOH or MSA methylsulfonic acid-   NaCl sodium chloride-   NaH sodium hydride-   NaHCO₃ sodium bicarbonate-   Na₂CO₃ sodium carbonate-   NaOH sodium hydroxide-   Na₂SO₃ sodium sulfite-   Na₂SO₄ sodium sulfate-   NBS N-bromosuccinimide-   NCS N-chlorosuccinimide-   NH₃ ammonia-   NH₄Cl ammonium chloride-   NH₄OH ammonium hydroxide-   NH₄COOH ammonium formate-   NMM N-methylmorpholine-   OTf triflate or trifluoromethanesulfonate-   Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium(0)-   Pd(OAc)₂ palladium(II) acetate-   Pd/C palladium on carbon-   Pd(dppf)Cl₂    [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II)-   Ph₃PCl₂ triphenylphosphine dichloride-   PG protecting group-   POCl₃ phosphorus oxychloride-   i-PrOH or IPA isopropanol-   PS Polystyrene-   rt room temperature-   SEM-Cl 2-(trimethysilyl)ethoxymethyl chloride-   SiO₂ silica oxide-   SnCl₂ tin(II) chloride-   TBAI tetra-n-butylammonium iodide-   TBN t-butyl nitrite-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   TMSCHN₂ trimethylsilyldiazomethane-   T3P® propane phosphonic acid anhydride-   TRIS tris (hydroxymethyl) aminomethane-   pTsOH p-toluenesulfonic acid

The compounds of the present invention can be prepared in a number ofways known to one skilled in the art of organic synthesis, which aredescribed in more detail in Section VI.

IV. Biology

While blood coagulation is essential to the regulation of an organism'shemostasis, it is also involved in many pathological conditions. Inthrombosis, a blood clot, or thrombus, may form and obstruct circulationlocally, causing ischemia and organ damage. Alternatively, in a processknown as embolism, the clot may dislodge and subsequently become trappedin a distal vessel, where it again causes ischemia and organ damage.Diseases arising from pathological thrombus formation are collectivelyreferred to as thromboembolic disorders and include acute coronarysyndrome, unstable angina, myocardial infarction, atrial fibrillation,thrombosis in the cavity of the heart, ischemic stroke, deep veinthrombosis, peripheral occlusive arterial disease, transient ischemicattack, and pulmonary embolism. In addition, thrombosis occurs onartificial surfaces in contact with blood, including catheters, stents,artificial heart valves, and hemodialysis membranes.

Some conditions contribute to the risk of developing thrombosis. Forexample, alterations of the vessel wall, changes in the flow of blood,and alterations in the composition of the vascular compartment. Theserisk factors are collectively known as Virchow's triad. (Colman, R. W.et al., eds., Hemostasis and Thrombosis, Basic Principles and ClinicalPractice, Fifth Edition, p. 853, Lippincott Williams & Wilkins (2006)).

Antithrombotic agents are frequently given to patients at risk ofdeveloping thromboembolic disease because of the presence of one or morepredisposing risk factors from Virchow's triad to prevent formation ofan occlusive thrombus (primary prevention). For example, in anorthopedic surgery setting (e.g., hip and knee replacement), anantithrombotic agent is frequently administered prior to a surgicalprocedure. The antithrombotic agent counterbalances the prothromboticstimulus exerted by vascular flow alterations (stasis), potentialsurgical vessel wall injury, as well as changes in the composition ofthe blood due to the acute phase response related to surgery. Anotherexample of the use of an antithrombotic agent for primary prevention isdosing with aspirin, a platelet activation inhibitor, in patients atrisk for developing thrombotic cardiovascular disease. Well recognizedrisk factors in this setting include age, male gender, hypertension,diabetes mellitus, lipid alterations, and obesity.

Antithrombotic agents are also indicated for secondary prevention,following an initial thrombotic episode. For example, patients withmutations in factor V (also known as factor V Leiden) and additionalrisk factors (e.g., pregnancy), are dosed with anticoagulants to preventthe reoccurrence of venous thrombosis. Another example entails secondaryprevention of cardiovascular events in patients with a history of acutemyocardial infarction or acute coronary syndrome. In a clinical setting,a combination of aspirin and clopidogrel (or other thienopyridines) maybe used to prevent a second thrombotic event.

Antithrombotic agents are also given to treat the disease state (i.e.,by arresting its development) after it has already started. For example,patients presenting with deep vein thrombosis are treated withanticoagulants (i.e., heparin, warfarin, or LMWH) to prevent furthergrowth of the venous occlusion. Over time, these agents also cause aregression of the disease state because the balance betweenprothrombotic factors and anticoagulant/profibrinolytic pathways ischanged in favor of the latter. Examples on the arterial vascular bedinclude the treatment of patients with acute myocardial infarction oracute coronary syndrome with aspirin and clopidogrel to prevent furthergrowth of vascular occlusions and eventually leading to a regression ofthrombotic occlusions.

Thus, antithrombotic agents are used widely for primary and secondaryprevention (i.e., prophylaxis or risk reduction) of thromboembolicdisorders, as well as treatment of an already existing thromboticprocess. Drugs that inhibit blood coagulation, or anticoagulants, are“pivotal agents for prevention and treatment of thromboembolicdisorders” (Hirsh, J. et al., Blood, 105:453-463 (2005)).

An alternative way of initiation of coagulation is operative when bloodis exposed to artificial surfaces (e.g., during hemodialysis, “on-pump”cardiovascular surgery, vessel grafts, bacterial sepsis), on cellsurfaces, cellular receptors, cell debris, DNA, RNA, and extracellularmatrices. This process is also termed contact activation. Surfaceabsorption of factor XII leads to a conformational change in the factorXII molecule, thereby facilitating activation to proteolytic activefactor XII molecules (factor XIIa and factor XIIf). Factor XIIa (orXIIf) has a number of target proteins, including plasma prekallikreinand factor XI. Active plasma kallikrein further activates factor XII,leading to an amplification of contact activation. Alternatively, theserine protease prolylcarboxylpeptidase can activate plasma kallikreincomplexed with high molecular weight kininogen in a multiprotein complexformed on the surface of cells and matrices (Shariat-Madar et al.,Blood, 108:192-199 (2006)). Contact activation is a surface mediatedprocess responsible in part for the regulation of thrombosis andinflammation, and is mediated, at least in part, by fibrinolytic-,complement-, kininogen/kinin-, and other humoral and cellular pathways(for review, Coleman, R., “Contact Activation Pathway”, Hemostasis andThrombosis, pp. 103-122, Lippincott Williams & Wilkins (2001); Schmaier,A. H., “Contact Activation”, Thrombosis and Hemorrhage, pp. 105-128(1998)). The biological relevance of the contact activation system forthromboembolic diseases is supported by the phenotype of factor XIIdeficient mice. More specifically, factor XII deficient mice wereprotected from thrombotic vascular occlusion in several thrombosismodels as well as stroke models and the phenotype of the XII deficientmice was identical to XI deficient mice (Renne et al., J. Exp. Med.,202:271-281 (2005); Kleinschmitz et al., J. Exp. Med., 203:513-518(2006)). The fact that factor XI is down-stream from factor XIIa,combined with the identical phenotype of the XII and XI deficient micesuggest that the contact activation system could play a major role infactor XI activation in vivo.

Factor XI is a zymogen of a trypsin-like serine protease and is presentin plasma at a relatively low concentration. Proteolytic activation atan internal R369-I370 bond yields a heavy chain (369 amino acids) and alight chain (238 amino acids). The latter contains a typicaltrypsin-like catalytic triad (H413, D464, and S557). Activation offactor XI by thrombin is believed to occur on negatively chargedsurfaces, most likely on the surface of activated platelets. Plateletscontain high affinity (0.8 nM) specific sites (130-500/platelet) foractivated factor XI. After activation, factor XIa remains surface boundand recognizes factor IX as its normal macromolecular substrate.(Galiani, D., Trends Cardiovasc. Med., 10:198-204 (2000)).

In addition to the feedback activation mechanisms described above,thrombin activates thrombin activated fibrinolysis inhibitor (TAFI), aplasma carboxypeptidase that cleaves C-terminal lysine and arginineresidues on fibrin, reducing the ability of fibrin to enhancetissue-type plasminogen activator (tPA) dependent plasminogenactivation. In the presence of antibodies to FXIa, clot lysis can occurmore rapidly independent of plasma TAFI concentration. (Bouma, B. N. etal., Thromb. Res., 101:329-354 (2001).) Thus, inhibitors of factor XIaare expected to be anticoagulant and profibrinolytic.

Further evidence for the anti-thromboembolic effects of targeting factorXI is derived from mice deficient in factor XI. It has been demonstratedthat complete fXI deficiency protected mice from ferric chloride(FeCl₃)-induced carotid artery thrombosis (Rosen et al., Thromb.Haemost., 87:774-777 (2002); Wang et al., J. Thromb. Haemost., 3:695-702(2005)). Also, factor XI deficiency rescues the perinatal lethalphenotype of complete protein C deficiency (Chan et al., Amer. J.Pathology, 158:469-479 (2001)). Furthermore, baboon cross-reactive,function blocking antibodies to human factor XI protect against baboonarterialvenous shunt thrombosis (Gruber et al., Blood, 102:953-955(2003)). Evidence for an antithrombotic effect of small moleculeinhibitors of factor XIa is also disclosed in published U.S. PatentPublication No. 2004/0180855 A1. Taken together, these studies suggestthat targeting factor XI will reduce the propensity for thrombotic andthromboembolic diseases.

Genetic evidence indicates that factor XI is not required for normalhomeostasis, implying a superior safety profile of the factor XImechanism compared to competing antithrombotic mechanisms. In contrastto hemophilia A (factor VIII deficiency) or hemophilia B (factor IXdeficiency), mutations of the factor XI gene causing factor XIdeficiency (hemophilia C) result in only a mild to moderate bleedingdiathesis characterized primarily by postoperative or posttraumatic, butrarely spontaneous hemorrhage. Postoperative bleeding occurs mostly intissue with high concentrations of endogenous fibrinolytic activity(e.g., oral cavity, and urogenital system). The majority of the casesare fortuitously identified by preoperative prolongation of aPTT(intrinsic system) without any prior bleeding history.

The increased safety of inhibition of XIa as an anticoagulation therapyis further supported by the fact that Factor XI knock-out mice, whichhave no detectable factor XI protein, undergo normal development, andhave a normal life span. No evidence for spontaneous bleeding has beennoted. The aPTT (intrinsic system) is prolonged in a gene dose-dependentfashion. Interestingly, even after severe stimulation of the coagulationsystem (tail transection), the bleeding time is not significantlyprolonged compared to wild-type and heterozygous litter mates. (Gailani,D., Frontiers in Bioscience, 6:201-207 (2001); Gailani, D. et al., BloodCoagulation and Fibrinolysis, 8:134-144 (1997).) Taken together, theseobservations suggest that high levels of inhibition of factor XIa shouldbe well tolerated. This is in contrast to gene targeting experimentswith other coagulation factors, excluding factor XII.

In vivo activation of factor XI can be determined by complex formationwith either C1 inhibitor or alpha 1 antitrypsin. In a study of 50patients with acute myocardial infarction (AMI), approximately 25% ofthe patients had values above the upper normal range of the complexELISA. This study can be viewed as evidence that at least in asubpopulation of patients with AMI, factor XI activation contributes tothrombin formation (Minnema, M. C. et al., Arterioscler. Thromb. Vasc.Biol., 20:2489-2493 (2000)). A second study establishes a positivecorrelation between the extent of coronary arteriosclerosis and factorXIa in complex with alpha 1 antitrypsin (Murakami, T. et al.,Arterioscler. Thromb. Vasc. Biol., 15:1107-1113 (1995)). In anotherstudy, Factor XI levels above the 90th percentile in patients wereassociated with a 2.2-fold increased risk for venous thrombosis(Meijers, J. C. M. et al., N. Engl. J Med., 342:696-701 (2000)).

Also, it is preferred to find new compounds with improved activity in invitro clotting assays, compared with known serine protease inhibitors,such as the activated partial thromboplastin time (aPTT) or prothrombintime (PT) assay. (for a description of the aPTT and PT assays see,Goodnight, S. H. et al., “Screening Tests of Hemostasis”, Disorders ofThrombosis and Hemostasis: A Clinical Guide, Second Edition, pp. 41-51,McGraw-Hill, New York (2001)).

It is also desirable and preferable to find compounds with advantageousand improved characteristics compared with known serine proteaseinhibitors, in one or more of the following categories that are given asexamples, and are not intended to be limiting: (a) pharmacokineticproperties, including oral bioavailability, half life, and clearance;(b) pharmaceutical properties; (c) dosage requirements; (d) factors thatdecrease blood concentration peak-to-trough characteristics; (e) factorsthat increase the concentration of active drug at the receptor; (f)factors that decrease the liability for clinical drug-drug interactions;(g) factors that decrease the potential for adverse side-effects,including selectivity versus other biological targets; and (h) factorsthat improve manufacturing costs or feasibility.

Pre-clinical studies demonstrated significant antithrombotic effects ofsmall molecule factor XIa inhibitors in rabbit and rat model of arterialand venous thrombosis, at doses that preserved hemostasis. Wong P. C. etal., Journal of Thrombosis and Thrombolysis, 32(2):129-137 (August2011); Schumacher, W. A. et al., Eur. J. Pharmacol., 167-174 (2007)).Furthermore, it was observed that in vitro prolongation of the aPTT byspecific XIa inhibitors is a good predictor of efficacy in ourthrombosis models. Thus, the in vitro aPTT test can be used as asurrogate for efficacy in vivo. Pre-clinical and clinical studies usingFXI antisense (ASO) has been shown to be effective in various venous andarterial thrombosis models, comparable to warfarin or enoxaparin withoutincreased bleeding (Bueller et al., DOI: 10.1056/NEJMoa1405760 (2014)).

As used herein, the term “patient” encompasses all mammalian species.

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)inhibiting the disease-state, i.e., arresting it development; and/or (b)relieving the disease-state, i.e., causing regression of the diseasestate.

As used herein, “prophylaxis” or “prevention” covers the preventivetreatment of a subclinical disease-state in a mammal, particularly in ahuman, aimed at reducing the probability of the occurrence of a clinicaldisease-state. Patients are selected for preventative therapy based onfactors that are known to increase risk of suffering a clinical diseasestate compared to the general population. “Prophylaxis” therapies can bedivided into (a) primary prevention and (b) secondary prevention.Primary prevention is defined as treatment in a subject that has not yetpresented with a clinical disease state, whereas secondary prevention isdefined as preventing a second occurrence of the same or similarclinical disease state.

As used herein, “risk reduction” covers therapies that lower theincidence of development of a clinical disease state. As such, primaryand secondary prevention therapies are examples of risk reduction.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention that is effective when administeredalone or in combination to inhibit factor XIa and/or plasma kallikreinand/or to prevent or treat the disorders listed herein. When applied toa combination, the term refers to combined amounts of the activeingredients that result in the preventive or therapeutic effect, whetheradministered in combination, serially, or simultaneously.

The term “thrombosis”, as used herein, refers to formation or presenceof a thrombus (pl. thrombi); clotting within a blood vessel that maycause ischemia or infarction of tissues supplied by the vessel. The term“embolism”, as used herein, refers to sudden blocking of an artery by aclot or foreign material that has been brought to its site of lodgmentby the blood current. The term “thromboembolism”, as used herein, refersto obstruction of a blood vessel with thrombotic material carried by theblood stream from the site of origin to plug another vessel. The term“thromboembolic disorders” entails both “thrombotic” and “embolic”disorders (defined above).

The term “thromboembolic disorders” as used herein includes arterialcardiovascular thromboembolic disorders, venous cardiovascular orcerebrovascular thromboembolic disorders, and thromboembolic disordersin the chambers of the heart or in the peripheral circulation. The term“thromboembolic disorders” as used herein also includes specificdisorders selected from, but not limited to, unstable angina or otheracute coronary syndromes, atrial fibrillation, first or recurrentmyocardial infarction, ischemic sudden death, transient ischemic attack,stroke, atherosclerosis, peripheral occlusive arterial disease, venousthrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism,coronary arterial thrombosis, cerebral arterial thrombosis, cerebralembolism, kidney embolism, pulmonary embolism, and thrombosis resultingfrom medical implants, devices, or procedures in which blood is exposedto an artificial surface that promotes thrombosis. The medical implantsor devices include, but are not limited to: prosthetic valves,artificial valves, indwelling catheters, stents, blood oxygenators,shunts, vascular access ports, ventricular assist devices and artificialhearts or heart chambers, and vessel grafts. The procedures include, butare not limited to: cardiopulmonary bypass, percutaneous coronaryintervention, and hemodialysis. In another embodiment, the term“thromboembolic disorders” includes acute coronary syndrome, stroke,deep vein thrombosis, and pulmonary embolism.

In another embodiment, the present invention provides a method for thetreatment of a thromboembolic disorder, wherein the thromboembolicdisorder is selected from unstable angina, an acute coronary syndrome,atrial fibrillation, myocardial infarction, transient ischemic attack,stroke, atherosclerosis, peripheral occlusive arterial disease, venousthrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism,coronary arterial thrombosis, cerebral arterial thrombosis, cerebralembolism, kidney embolism, pulmonary embolism, and thrombosis resultingfrom medical implants, devices, or procedures in which blood is exposedto an artificial surface that promotes thrombosis. In anotherembodiment, the present invention provides a method for the treatment ofa thromboembolic disorder, wherein the thromboembolic disorder isselected from acute coronary syndrome, stroke, venous thrombosis, atrialfibrillation, and thrombosis resulting from medical implants anddevices.

In another embodiment, the present invention provides a method for theprimary prophylaxis of a thromboembolic disorder, wherein thethromboembolic disorder is selected from unstable angina, an acutecoronary syndrome, atrial fibrillation, myocardial infarction, ischemicsudden death, transient ischemic attack, stroke, atherosclerosis,peripheral occlusive arterial disease, venous thrombosis, deep veinthrombosis, thrombophlebitis, arterial embolism, coronary arterialthrombosis, cerebral arterial thrombosis, cerebral embolism, kidneyembolism, pulmonary embolism, and thrombosis resulting from medicalimplants, devices, or procedures in which blood is exposed to anartificial surface that promotes thrombosis. In another embodiment, thepresent invention provides a method for the primary prophylaxis of athromboembolic disorder, wherein the thromboembolic disorder is selectedfrom acute coronary syndrome, stroke, venous thrombosis, and thrombosisresulting from medical implants and devices.

In another embodiment, the present invention provides a method for thesecondary prophylaxis of a thromboembolic disorder, wherein thethromboembolic disorder is selected from unstable angina, an acutecoronary syndrome, atrial fibrillation, recurrent myocardial infarction,transient ischemic attack, stroke, atherosclerosis, peripheral occlusivearterial disease, venous thrombosis, deep vein thrombosis,thrombophlebitis, arterial embolism, coronary arterial thrombosis,cerebral arterial thrombosis, cerebral embolism, kidney embolism,pulmonary embolism, and thrombosis resulting from medical implants,devices, or procedures in which blood is exposed to an artificialsurface that promotes thrombosis. In another embodiment, the presentinvention provides a method for the secondary prophylaxis of athromboembolic disorder, wherein the thromboembolic disorder is selectedfrom acute coronary syndrome, stroke, atrial fibrillation and venousthrombosis.

The term “stroke”, as used herein, refers to embolic stroke oratherothrombotic stroke arising from occlusive thrombosis in the carotidcommunis, carotid interna, or intracerebral arteries.

It is noted that thrombosis includes vessel occlusion (e.g., after abypass) and reocclusion (e.g., during or after percutaneous transluminalcoronary angioplasty). The thromboembolic disorders may result fromconditions including but not limited to atherosclerosis, surgery orsurgical complications, prolonged immobilization, arterial fibrillation,congenital thrombophilia, cancer, diabetes, effects of medications orhormones, and complications of pregnancy.

Thromboembolic disorders are frequently associated with patients withatherosclerosis. Risk factors for atherosclerosis include but are notlimited to male gender, age, hypertension, lipid disorders, and diabetesmellitus. Risk factors for atherosclerosis are at the same time riskfactors for complications of atherosclerosis, i.e., thromboembolicdisorders.

Similarly, arterial fibrillation is frequently associated withthromboembolic disorders. Risk factors for arterial fibrillation andsubsequent thromboembolic disorders include cardiovascular disease,rheumatic heart disease, nonrheumatic mitral valve disease, hypertensivecardiovascular disease, chronic lung disease, and a variety ofmiscellaneous cardiac abnormalities as well as thyrotoxicosis.

Diabetes mellitus is frequently associated with atherosclerosis andthromboembolic disorders. Risk factors for the more common type 2include but are not limited to are family history, obesity, physicalinactivity, race/ethnicity, previously impaired fasting glucose orglucose tolerance test, history of gestational diabetes mellitus ordelivery of a “big baby”, hypertension, low HDL cholesterol, andpolycystic ovary syndrome.

Risk factors for congenital thrombophilia include gain of functionmutations in coagulation factors or loss of function mutations in theanticoagulant- or fibrinolytic pathways.

Thrombosis has been associated with a variety of tumor types, e.g.,pancreatic cancer, breast cancer, brain tumors, lung cancer, ovariancancer, prostate cancer, gastrointestinal malignancies, and Hodgkins ornon-Hodgkins lymphoma. Recent studies suggest that the frequency ofcancer in patients with thrombosis reflects the frequency of aparticular cancer type in the general population (Levitan, N. et al.,Medicine (Baltimore), 78(5):285-291 (1999); Levine M. et al., N. Engl.J. Med., 334(11):677-681 (1996); Blom, J. W. et al., JAMA,293(6):715-722 (2005)). Hence, the most common cancers associated withthrombosis in men are prostate, colorectal, brain, and lung cancer, andin women are breast, ovary, and lung cancer. The observed rate of venousthromboembolism (VTE) in cancer patients is significant. The varyingrates of VTE between different tumor types are most likely related tothe selection of the patient population. Cancer patients at risk forthrombosis may possess any or all of the following risk factors: (i) thestage of the cancer (i.e., presence of metastases), (ii) the presence ofcentral vein catheters, (iii) surgery and anticancer therapies includingchemotherapy, and (iv) hormones and antiangiogenic drugs. Thus, it iscommon clinical practice to dose patients having advanced tumors withheparin or low molecular heparin to prevent thromboembolic disorders. Anumber of low molecular heparin preparations have been approved by theFDA for these indications.

There are three main clinical situations when considering the preventionof VTE in a medical cancer patient: (i) the patient is bedridden forprolonged periods of time; (ii) the ambulatory patient is receivingchemotherapy or radiation; and (iii) the patient is with indwellingcentral vein catheters. Unfractionated heparin (UFH) and low molecularweight heparin (LMWH) are effective antithrombotic agents in cancerpatients undergoing surgery. (Mismetti, P. et al., British Journal ofSurgery, 88:913-930 (2001).)

A. In Vitro Assays

The effectiveness of compounds of the present invention as inhibitors ofthe coagulation Factors XIa, VIIa, IXa, Xa, XIIa, plasma kallikrein orthrombin, can be determined using a relevant purified serine protease,respectively, and an appropriate synthetic substrate. The rate ofhydrolysis of the chromogenic or fluorogenic substrate by the relevantserine protease was measured both in the absence and presence ofcompounds of the present invention. Hydrolysis of the substrate resultedin the release of pNA (para nitroaniline), which was monitoredspectrophotometrically by measuring the increase in absorbance at 405nm, or the release of AMC (amino methylcoumarin), which was monitoredspectrofluorometrically by measuring the increase in emission at 460 nmwith excitation at 380 nm. A decrease in the rate of absorbance orfluorescence change in the presence of inhibitor is indicative of enzymeinhibition. Such methods are known to one skilled in the art. Theresults of this assay are expressed as the inhibitory constant, K_(i).

Factor XIa determinations were made in 50 mM HEPES buffer at pH 7.4containing 145 mM NaCl, 5 mM KCl, and 0.1% PEG 8000 (polyethyleneglycol; JT Baker or Fisher Scientific). Determinations were made usingpurified human Factor XIa at a final concentration of 25-200 pM(Haematologic Technologies) and the synthetic substrate S-2366(pyroGlu-Pro-Arg-pNA; Chromogenix or AnaSpec) at a concentration of0.0002-0.001 M.

Factor VIIa determinations were made in 0.005 M calcium chloride, 0.15 Msodium chloride, 0.05 M HEPES buffer containing 0.1% PEG 8000 at a pH of7.5. Determinations were made using purified human Factor VIIa(Haematologic Technologies) or recombinant human Factor VIIa (NovoNordisk) at a final assay concentration of 0.5-10 nM, recombinantsoluble tissue factor at a concentration of 10-40 nM and the syntheticsubstrate H-D-Ile-Pro-Arg-pNA (S-2288; Chromogenix or BMPM-2; AnaSpec)at a concentration of 0.001-0.0075 M.

Factor IXa determinations were made in 0.005 M calcium chloride, 0.1 Msodium chloride, 0.0000001 M Refludan (Berlex), 0.05 M TRIS base and0.5% PEG 8000 at a pH of 7.4. Refludan was added to inhibit smallamounts of thrombin in the commercial preparations of human Factor IXa.Determinations were made using purified human Factor IXa (HaematologicTechnologies) at a final assay concentration of 20-100 nM and thesynthetic substrate PCIXA2100-B (CenterChem) or Pefafluor IXa 3688(H-D-Leu-Ph′Gly-Arg-AMC; CenterChem) at a concentration of 0.0004-0.0005M.

Factor Xa determinations were made in 0.1 M sodium phosphate buffer at apH of 7.5 containing 0.2 M sodium chloride and 0.5% PEG 8000.Determinations were made using purified human Factor Xa (HaematologicTechnologies) at a final assay concentration of 150-1000 pM and thesynthetic substrate S-2222 (Bz-Ile-Glu (gamma-OMe, 50%)-Gly-Arg-pNA;Chromogenix) at a concentration of 0.0002-0.00035 M.

Factor XIIa determinations were made in 0.05 M HEPES buffer at pH 7.4containing 0.145 M NaCl, 0.05 M KCl, and 0.1% PEG 8000. Determinationswere made using purified human Factor XIIa at a final concentration of 4nM (American Diagnostica) and the synthetic substrate SPECTROZYME® #312(H-D-CHT-Gly-L-Arg-pNA.2AcOH; American Diagnostica) at a concentrationof 0.00015 M.

Plasma kallikrein determinations were made in 0.1 M sodium phosphatebuffer at a pH of 7.5 containing 0.1-0.2 M sodium chloride and 0.5% PEG8000. Determinations were made using purified human plasma kallikrein(Enzyme Research Laboratories) at a final assay concentration of 200 pMand the synthetic substrate S-2302 (H-(D)-Pro-Phe-Arg-pNA; Chromogenix)at a concentration of 0.00008-0.0004 M.

Thrombin determinations were made in 0.1 M sodium phosphate buffer at apH of 7.5 containing 0.2 M sodium chloride and 0.5% PEG 8000.Determinations were made using purified human alpha thrombin(Haematologic Technologies or Enzyme Research Laboratories) at a finalassay concentration of 200-250 pM and the synthetic substrate S-2366(pyroGlu-Pro-Arg-pNA; Chromogenix or AnaSpec) at a concentration of0.0002-0.0004 M.

The Michaelis constant, K_(m), for substrate hydrolysis by eachprotease, was determined at 25° C. or 37° C. in the absence ofinhibitor. Values of K_(i) were determined by allowing the protease toreact with the substrate in the presence of the inhibitor. Reactionswere allowed to go for periods of 20-180 minutes (depending on theprotease) and the velocities (rate of absorbance or fluorescence changeversus time) were measured. The following relationships were used tocalculate K_(i) values:

(V _(max) *S)/(K _(m) +S)

(v _(o) −v _(s))/v _(s) =I/(K _(i)(1+S/K _(m))) for a competitiveinhibitor with one binding site; or

v _(s) /v _(o) =A+((B−A)/1+((IC ₅₀/(I)^(n)))); and

K _(i) =IC ₅₀/(1+S/K _(m)) for a competitive inhibitor

where:

v_(o) is the velocity of the control in the absence of inhibitor;

v_(s) is the velocity in the presence of inhibitor;

V_(max) is the maximum reaction velocity;

I is the concentration of inhibitor;

A is the minimum activity remaining (usually locked at zero);

B is the maximum activity remaining (usually locked at 1.0);

n is the Hill coefficient, a measure of the number and cooperativity ofpotential inhibitor binding sites;

IC₅₀ is the concentration of inhibitor that produces 50% inhibitionunder the assay conditions;

K_(i) is the dissociation constant of the enzyme: inhibitor complex;

S is the concentration of substrate; and

K_(m) is the Michaelis constant for the substrate.

The selectivity of a compound may be evaluated by taking the ratio ofthe K_(i) value for a given protease with the K_(i) value for theprotease of interest (i.e., selectivity for FXIa versus protease P=K_(i)for protease P/K_(i) for FXIa). Compounds with selectivity ratios >20are considered selective.

The effectiveness of compounds of the present invention as inhibitors ofcoagulation can be determined using a standard or modified clottingassay. An increase in the plasma clotting time in the presence ofinhibitor is indicative of anticoagulation. Relative clotting time isthe clotting time in the presence of an inhibitor divided by theclotting time in the absence of an inhibitor. The results of this assaymay be expressed as IC1.5× or IC2×, the inhibitor concentration requiredto increase the clotting time by 1.5-times or 2-times, respectively,relative to the clotting time in the absence of the inhibitor.

The IC1.5× or IC2× is found by linear interpolation from relativeclotting time versus inhibitor concentration plots using inhibitorconcentration that spans the IC1.5× or IC2×.

Clotting times are determined using citrated normal human plasma as wellas plasma obtained from a number of laboratory animal species (e.g., rator rabbit). A compound is diluted into plasma beginning with a 10 mMDMSO stock solution. The final concentration of DMSO is less than 2%.Plasma clotting assays are performed in an automated coagulationanalyzer (Sysmex, Dade-Behring, Ill.). Similarly, clotting times can bedetermined from laboratory animal species or humans dosed with compoundsof the invention.

Activated Partial Thromboplastin Time (aPTT) is determined using ACTIN®(Dade-Behring, Ill.) following the directions in the package insert.Plasma (0.05 mL) is warmed to 37° C. for 1 minute. ACTIN® (0.05 mL) isadded to the plasma and incubated for an additional 2 to 5 minutes.Calcium chloride (25 mM, 0.05 mL) is added to the reaction to initiatecoagulation. The clotting time is the time in seconds from the momentcalcium chloride is added until a clot is detected.

Prothrombin Time (PT) is determined using thromboplastin (ThromboplastinC Plus or Innovin, Dade-Behring, Ill.) following the directions in thepackage insert. Plasma (0.05 mL) is warmed to 37° C. for 1 minute.Thromboplastin (0.1 mL) is added to the plasma to initiate coagulation.The clotting time is the time in seconds from the moment thromboplastinis added until a clot is detected.

Chymotrypsin determinations were made in 50 mM HEPES buffer at pH 7.4containing 145 mM NaCl, 5 mM KCl, and 0.1% PEG 8000 (polyethyleneglycol; JT Baker or Fisher Scientific). Determinations were made usingpurified human chymotrypsin at a final concentration of 0.2-2 nM(Calbiochem) and the synthetic substrate S-2586(Methoxy-Succinyl-Arg-Pro-Tyr-pNA; Chromogenix) at a concentration of0.0005-0.005 M.

Trypsin determinations were made in 0.1 M sodium phosphate buffer at apH of 7.5 containing 0.2 M sodium chloride and 0.5% PEG 8000.Determinations were made using purified human trypsin (Sigma) at a finalassay concentration of 0.1-1 nM and the synthetic substrate S-2222(Bz-Ile-Glu (gamma-OMe, 50%)-Gly-Arg-pNA; Chromogenix) at aconcentration of 0.0005-0.005 M.

The exemplified Examples disclosed below were tested in the Factor XIaassay described above and found having Factor XIa inhibitory activity. Arange of Factor XIa inhibitory activity (Ki values) of ≦10 μM (10000 nM)was observed.

The exemplified Examples disclosed below were tested in the PlasmaKallikrein assay described above, with some Examples having both FactorXIa and Plasma Kallikrein inhibitory activity. For those Examples wherethe Plasma Kallikrein inhibitory activity was observed as a (Ki values)of ≦10 μM (10000 nM), the inhibitory activity is reported.

The exemplified Examples disclosed below were tested in the PlasmaKallikrein assay described above, with some Examples having both FactorXIa and Plasma Kallikrein inhibitory activity. For those Examples wherethe Plasma Kallikrein inhibitory activity was observed as Ki values of≦10 μM (10000 nM), the inhibitory activity is reported.

The compounds of the present invention exhibit unexpected FXIainhibitory activity compared to the compounds of Formula (X) in WO2014/022767 A1 wherein ring B is a pyrazole connected through its carbonatoms to the macrocycle. For example, WO 2014/022767 discloses Example221 at page 319 with the following chemical structure

and with a factor XIa Ki value of 1317 nM (Table 1, page 89). Incontrast, the factor XIa Ki values of the compounds of the presentinvention as shown at the end of each example are less than 20 nM. Thesedata illustrate that the compounds of the invention herein, e.g.,compounds of Formulae (I), (II), (III), (Ia), (IIa), (IIIa), (IV), and(V) are surprisingly advantageous in inhibiting factor XIa.

B. In Vivo Assays

The effectiveness of compounds of the present invention asantithrombotic agents can be determined using relevant in vivothrombosis models, including In Vivo Electrically-induced Carotid ArteryThrombosis Models and In Vivo Rabbit Arteriovenous Shunt ThrombosisModels.

a. In Vivo Electrically-Induced Carotid Artery Thrombosis (ECAT) Model

The rabbit ECAT model, described by Wong et al. (J. Pharmacol. Exp.Ther., 295:212-218 (2000)), can be used in this study. Male New ZealandWhite rabbits are anesthetized with ketamine (50 mg/kg+50 mg/kg/h IM)and xylazine (10 mg/kg+10 mg/kg/h IM). These anesthetics aresupplemented as needed. An electromagnetic flow probe is placed on asegment of an isolated carotid artery to monitor blood flow. Test agentsor vehicle will be given (i.v., i.p., s.c., or orally) prior to or afterthe initiation of thrombosis. Drug treatment prior to initiation ofthrombosis is used to model the ability of test agents to prevent andreduce the risk of thrombus formation, whereas dosing after initiationis used to model the ability to treat existing thrombotic disease.Thrombus formation is induced by electrical stimulation of the carotidartery for 3 min at 4 mA using an external stainless-steel bipolarelectrode. Carotid blood flow is measured continuously over a 90-minperiod to monitor thrombus-induced occlusion. Total carotid blood flowover 90 min is calculated by the trapezoidal rule. Average carotid flowover 90 min is then determined by converting total carotid blood flowover 90 min to percent of total control carotid blood flow, which wouldresult if control blood flow had been maintained continuously for 90min. The ED₅₀ (dose that increased average carotid blood flow over 90min to 50% of the control) of compounds are estimated by a nonlinearleast square regression program using the Hill sigmoid E_(max) equation(DeltaGraph; SPSS Inc., Chicago, Ill.).

b. In Vivo Rabbit Arteriovenous (AV) Shunt Thrombosis Model

The rabbit AV shunt model, described by Wong et al. (Wong, P. C. et al.,J. Pharmacol. Exp. Ther. 292:351-357 (2000)), can be used in this study.Male New Zealand White rabbits are anesthetized with ketamine (50mg/kg+50 mg/kg/h IM) and xylazine (10 mg/kg+10 mg/kg/h IM). Theseanesthetics are supplemented as needed. The femoral artery, jugular veinand femoral vein are isolated and catheterized. A saline-filled AV shuntdevice is connected between the femoral arterial and the femoral venouscannulae. The AV shunt device consists of an outer piece of tygon tubing(length=8 cm; internal diameter=7.9 mm) and an inner piece of tubing(length=2.5 cm; internal diameter=4.8 mm). The AV shunt also contains an8-cm-long 2-0 silk thread (Ethicon, Somerville, N.J.). Blood flows fromthe femoral artery via the AV-shunt into the femoral vein. The exposureof flowing blood to a silk thread induces the formation of a significantthrombus. Forty minutes later, the shunt is disconnected and the silkthread covered with thrombus is weighed. Test agents or vehicle will begiven (i.v., i.p., s.c., or orally) prior to the opening of the AVshunt. The percentage inhibition of thrombus formation is determined foreach treatment group. The ID₅₀ values (dose that produces 50% inhibitionof thrombus formation) are estimated by a nonlinear least squareregression program using the Hill sigmoid E_(max) equation (DeltaGraph;SPSS Inc., Chicago, Ill.).

The anti-inflammatory effect of these compounds can be demonstrated inan Evans Blue dye extravasation assay using C1-esterase inhibitordeficient mice. In this model, mice are dosed with a compound of thepresent invention, Evans Blue dye is injected via the tail vein, andextravasation of the blue dye is determined by spectrophotometric meansfrom tissue extracts.

The ability of the compounds of the current invention to reduce orprevent the systemic inflammatory response syndrome, for example, asobserved during on-pump cardiovascular procedures, can be tested in invitro perfusion systems, or by on-pump surgical procedures in largermammals, including dogs and baboons. Read-outs to assess the benefit ofthe compounds of the present invention include for example reducedplatelet loss, reduced platelet/white blood cell complexes, reducedneutrophil elastase levels in plasma, reduced activation of complementfactors, and reduced activation and/or consumption of contact activationproteins (plasma kallikrein, factor XII, factor XI, high molecularweight kininogen, C1-esterase inhibitors).

The compounds of the present invention may also be useful as inhibitorsof additional serine proteases, notably human thrombin, human plasmakallikrein and human plasmin. Because of their inhibitory action, thesecompounds are indicated for use in the prevention or treatment ofphysiological reactions, including blood coagulation, fibrinolysis,blood pressure regulation and inflammation, and wound healing catalyzedby the aforesaid class of enzymes. Specifically, the compounds haveutility as drugs for the treatment of diseases arising from elevatedthrombin activity of the aforementioned serine proteases, such asmyocardial infarction, and as reagents used as anticoagulants in theprocessing of blood to plasma for diagnostic and other commercialpurposes.

V. Pharmaceutical Compositions, Formulations and Combinations

The compounds of this invention can be administered in such oral dosageforms as tablets, capsules (each of which includes sustained release ortimed release formulations), pills, powders, granules, elixirs,tinctures, suspensions, syrups, and emulsions. They may also beadministered in intravenous (bolus or infusion), intraperitoneal,subcutaneous, or intramuscular form, all using dosage forms well knownto those of ordinary skill in the pharmaceutical arts. They can beadministered alone, but generally will be administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

The term “pharmaceutical composition” means a composition comprising acompound of the invention in combination with at least one additionalpharmaceutically acceptable carrier. A “pharmaceutically acceptablecarrier” refers to media generally accepted in the art for the deliveryof biologically active agents to animals, in particular, mammals,including, i.e., adjuvant, excipient or vehicle, such as diluents,preserving agents, fillers, flow regulating agents, disintegratingagents, wetting agents, emulsifying agents, suspending agents,sweetening agents, flavoring agents, perfuming agents, antibacterialagents, antifungal agents, lubricating agents and dispensing agents,depending on the nature of the mode of administration and dosage forms.

Pharmaceutically acceptable carriers are formulated according to anumber of factors well within the purview of those of ordinary skill inthe art. These include, without limitation: the type and nature of theactive agent being formulated; the subject to which the agent-containingcomposition is to be administered; the intended route of administrationof the composition; and the therapeutic indication being targeted.Pharmaceutically acceptable carriers include both aqueous andnon-aqueous liquid media, as well as a variety of solid and semi-soliddosage forms. Such carriers can include a number of differentingredients and additives in addition to the active agent, suchadditional ingredients being included in the formulation for a varietyof reasons, e.g., stabilization of the active agent, binders, etc., wellknown to those of ordinary skill in the art. Descriptions of suitablepharmaceutically acceptable carriers, and factors involved in theirselection, are found in a variety of readily available sources such as,for example, Remington's Pharmaceutical Sciences, 18th Edition (1990).

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient, and theeffect desired. A physician or veterinarian can determine and prescribethe effective amount of the drug required to prevent, counter, or arrestthe progress of the thromboembolic disorder.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to about 1000 mg/kg of body weight, preferably between about0.01 to about 100 mg/kg of body weight per day, and most preferablybetween about 0.1 to about 20 mg/kg/day. Intravenously, the mostpreferred doses will range from about 0.001 to about 10 mg/kg/minuteduring a constant rate infusion. Compounds of this invention may beadministered in a single daily dose, or the total daily dosage may beadministered in divided doses of two, three, or four times daily.

Compounds of this invention can also be administered by parenteraladministration (e.g., intra-venous, intra-arterial, intramuscularly, orsubcutaneously. When administered intra-venous or intra-arterial, thedose can be given continuously or intermittent. Furthermore, formulationcan be developed for intramuscularly and subcutaneous delivery thatensure a gradual release of the active pharmaceutical ingredient. In oneembodiment, the pharmaceutical composition is a solid formulation, e.g.,a spray-dried composition, which may be used as is, or whereto thephysician or the patient adds solvents, and/or diluents prior to use.

Compounds of this invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal routes,using transdermal skin patches. When administered in the form of atransdermal delivery system, the dosage administration will, of course,be continuous rather than intermittent throughout the dosage regimen.

The compounds are typically administered in admixture with suitablepharmaceutical diluents, excipients, or carriers (collectively referredto herein as pharmaceutical carriers) suitably selected with respect tothe intended form of administration, e.g., oral tablets, capsules,elixirs, and syrups, and consistent with conventional pharmaceuticalpractices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl cellulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels. Soliddispersions are also called solid-state dispersions. In someembodiments, any compound described herein is formulated as a spraydried dispersion (SDD). An SDD is a single phase amorphous moleculardispersion of a drug in a polymer matrix. It is a solid solutionprepared by dissolving the drug and a polymer in a solvent (e.g.,acetone, methanol or the like) and spray drying the solution. Thesolvent rapidly evaporates from droplets which rapidly solidifies thepolymer and drug mixture trapping the drug in amorphous form as anamorphous molecular dispersion.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 1000 milligrams of activeingredient per dosage unit. In these pharmaceutical compositions theactive ingredient will ordinarily be present in an amount of about0.1-95% by weight based on the total weight of the composition.

Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like.

Similar diluents can be used to make compressed tablets. Both tabletsand capsules can be manufactured as sustained release products toprovide for continuous release of medication over a period of hours.Compressed tablets can be sugar coated or film coated to mask anyunpleasant taste and protect the tablet from the atmosphere, or entericcoated for selective disintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration preferably contain a watersoluble salt of the active ingredient, suitable stabilizing agents, andif necessary, buffer substances. Antioxidizing agents such as sodiumbisulfite, sodium sulfite, or ascorbic acid, either alone or combined,are suitable stabilizing agents. Also used are citric acid and its saltsand sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl- or propyl-paraben,and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field.

Where the compounds of this invention are combined with otheranticoagulant agents, for example, a daily dosage may be about 0.1 toabout 100 milligrams of the compound of the present invention and about0.1 to about 100 milligrams per kilogram of patient body weight. For atablet dosage form, the compounds of this invention generally may bepresent in an amount of about 5 to about 300 milligrams per dosage unit,and the second anticoagulant in an amount of about 1 to about 500milligrams per dosage unit.

Where the compounds of the present invention are administered incombination with an anti-platelet agent, by way of general guidance,typically a daily dosage may be about 0.01 to about 300 milligrams ofthe compound of the present invention and about 50 to about 150milligrams of the anti-platelet agent, preferably about 0.1 to about 4milligrams of the compound of the present invention and about 1 to about3 milligrams of antiplatelet agents, per kilogram of patient bodyweight.

Where the compounds of the present invention are administered incombination with thrombolytic agent, typically a daily dosage may beabout 0.1 to about 100 milligrams of the compound of the presentinvention, per kilogram of patient body weight and, in the case of thethrombolytic agents, the usual dosage of the thrombolytic agent whenadministered alone may be reduced by about 50-80% when administered witha compound of the present invention.

Particularly when provided as a single dosage unit, the potential existsfor a chemical interaction between the combined active ingredients. Forthis reason, when the compound of the present invention and a secondtherapeutic agent are combined in a single dosage unit they areformulated such that although the active ingredients are combined in asingle dosage unit, the physical contact between the active ingredientsis minimized (that is, reduced). For example, one active ingredient maybe enteric coated. By enteric coating one of the active ingredients, itis possible not only to minimize the contact between the combined activeingredients, but also, it is possible to control the release of one ofthese components in the gastrointestinal tract such that one of thesecomponents is not released in the stomach but rather is released in theintestines. One of the active ingredients may also be coated with amaterial that affects a sustained-release throughout thegastrointestinal tract and also serves to minimize physical contactbetween the combined active ingredients. Furthermore, thesustained-released component can be additionally enteric coated suchthat the release of this component occurs only in the intestine. Stillanother approach would involve the formulation of a combination productin which the one component is coated with a sustained and/or entericrelease polymer, and the other component is also coated with a polymersuch as a low viscosity grade of hydroxypropyl methylcellulose (HPMC) orother appropriate materials as known in the art, in order to furtherseparate the active components. The polymer coating serves to form anadditional barrier to interaction with the other component.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

In another embodiment, the present invention provides a pharmaceuticalcomposition further comprising additional therapeutic agent(s) selectedfrom potassium channel openers, potassium channel blockers, calciumchannel blockers, sodium hydrogen exchanger inhibitors, antiarrhythmicagents, antiatherosclerotic agents, anticoagulants, antithromboticagents, prothrombolytic agents, fibrinogen antagonists, diuretics,antihypertensive agents, ATPase inhibitors, mineralocorticoid receptorantagonists, phospodiesterase inhibitors, antidiabetic agents,anti-inflammatory agents, antioxidants, angiogenesis modulators,antiosteoporosis agents, hormone replacement therapies, hormone receptormodulators, oral contraceptives, antiobesity agents, antidepressants,antianxiety agents, antipsychotic agents, antiproliferative agents,antitumor agents, antiulcer and gastroesophageal reflux disease agents,growth hormone agents and/or growth hormone secretagogues, thyroidmimetics, anti-infective agents, antiviral agents, antibacterial agents,antifungal agents, cholesterol/lipid lowering agents and lipid profiletherapies, and agents that mimic ischemic preconditioning and/ormyocardial stunning, or a combination thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition further comprising additional therapeutic agent(s) selectedfrom an anti-arrhythmic agent, an anti-hypertensive agent, ananticoagulant agent, an anti-platelet agent, a thrombin inhibitingagent, a thrombolytic agent, a fibrinolytic agent, a calcium channelblocker, a potassium channel blocker, a cholesterol/lipid loweringagent, or a combination thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition further comprising additional therapeutic agent(s) selectedfrom warfarin, unfractionated heparin, low molecular weight heparin,synthetic pentasaccharide, hirudin, argatroban, aspirin, ibuprofen,naproxen, sulindac, indomethacin, mefenamate, dipyridamol, droxicam,diclofenac, sulfinpyrazone, piroxicam, ticlopidine, clopidogrel,tirofiban, eptifibatide, abciximab, melagatran, ximelagatran,disulfatohirudin, tissue plasminogen activator, modified tissueplasminogen activator, anistreplase, urokinase, and streptokinase, or acombination thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition wherein the additional therapeutic agent is anantihypertensive agent selected from ACE inhibitors, AT-1 receptorantagonists, beta-adrenergic receptor antagonists, ETA receptorantagonists, dual ETA/AT-1 receptor antagonists, renin inhibitors(aliskerin) and vasopepsidase inhibitors, an antiarrythmic agentselected from I_(Kur) inhibitors, an anticoagulant selected fromthrombin inhibitors, antithrombin-III activators, heparin co-factor IIactivators, other factor XIa inhibitors, other kallikrein inhibitors,plasminogen activator inhibitor (PAI-1) antagonists, thrombinactivatable fibrinolysis inhibitor (TAFI) inhibitors, factor VIIainhibitors, factor IXa inhibitors, and factor Xa inhibitors, or anantiplatelet agent selected from GPIIb/IIIa blockers, GP Ib/IX blockers,protease activated receptor 1 (PAR-1) antagonists, protease activatedreceptor4 (PAR-4) antagonists, prostaglandin E2 receptor EP3antagonists, collagen receptor antagonists, phosphodiesterase-IIIinhibitors, P2Y₁ receptor antagonists, P2Y₁₂ antagonists, thromboxanereceptor antagonists, cyclooxygense-1 inhibitors, and aspirin, or acombination thereof.

In another embodiment, the present invention provides pharmaceuticalcomposition, wherein the additional therapeutic agent(s) are ananti-platelet agent or a combination thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition, wherein the additional therapeutic agent is theanti-platelet agent clopidogrel.

The compounds of the present invention can be administered alone or incombination with one or more additional therapeutic agents. By“administered in combination” or “combination therapy” it is meant thatthe compound of the present invention and one or more additionaltherapeutic agents are administered concurrently to the mammal beingtreated. When administered in combination, each component may beadministered at the same time or sequentially in any order at differentpoints in time. Thus, each component may be administered separately butsufficiently closely in time so as to provide the desired therapeuticeffect.

Compounds that can be administered in combination with the compounds ofthe present invention include, but are not limited to, anticoagulants,anti-thrombin agents, anti-platelet agents, fibrinolytics, hypolipidemicagents, antihypertensive agents, and anti-ischemic agents.

Other anticoagulant agents (or coagulation inhibitory agents) that maybe used in combination with the compounds of this invention includewarfarin, heparin (either unfractionated heparin or any commerciallyavailable low molecular weight heparin, for example LOVENOX®), syntheticpentasaccharide, direct acting thrombin inhibitors including hirudin andargatroban, as well as other factor VIIa inhibitors, factor IXainhibitors, factor Xa inhibitors (e.g., ARIXTRA®, apixaban, rivaroxaban,LY-517717, DU-176b, DX-9065a, and those disclosed in WO 98/57951, WO03/026652, WO 01/047919, and WO 00/076970), factor XIa inhibitors, andinhibitors of activated TAFI and PAI-1 known in the art.

The term anti-platelet agents (or platelet inhibitory agents), as usedherein, denotes agents that inhibit platelet function, for example, byinhibiting the aggregation, adhesion or granule-content secretion ofplatelets. Such agents include, but are not limited to, the variousknown non-steroidal anti-inflammatory drugs (NSAIDs) such asacetaminophen, aspirin, codeine, diclofenac, droxicam, fentaynl,ibuprofen, indomethacin, ketorolac, mefenamate, morphine, naproxen,phenacetin, piroxicam, sufentanyl, sulfinpyrazone, sulindac, andpharmaceutically acceptable salts or prodrugs thereof. Of the NSAIDs,aspirin (acetylsalicylic acid or ASA) and piroxicam are preferred. Othersuitable platelet inhibitory agents include glycoprotein IIb/IIIaantagonists (e.g., tirofiban, eptifibatide, abciximab, and integrelin),thromboxane-A2-receptor antagonists (e.g., ifetroban),thromboxane-A-synthetase inhibitors, phosphodiesterase-III (PDE-III)inhibitors (e.g., dipyridamole, cilostazol), and PDE-V inhibitors (suchas sildenafil), protease-activated receptor 1 (PAR-1) antagonists (e.g.,E-5555, SCH-530348, SCH-203099, SCH-529153 and SCH-205831), andpharmaceutically acceptable salts or prodrugs thereof.

Other examples of suitable anti-platelet agents for use in combinationwith the compounds of the present invention, with or without aspirin,are ADP (adenosine diphosphate) receptor antagonists, preferablyantagonists of the purinergic receptors P2Y₁ and P2Y₁₂, with P2Y₁₂ beingeven more preferred. Preferred P2Y₁₂ receptor antagonists includeclopidogrel, ticlopidine, prasugrel, ticagrelor, and cangrelor, andpharmaceutically acceptable salts or prodrugs thereof. Ticlopidine andclopidogrel are also preferred compounds since they are known to be moregentle than aspirin on the gastrointestinal tract in use. Clopidogrel isan even more preferred agent.

A preferred example is a triple combination of a compound of the presentinvention, aspirin, and another anti-platelet agent. Preferably, theanti-platelet agent is clopidogrel or prasugrel, more preferablyclopidogrel.

The term thrombin inhibitors (or anti-thrombin agents), as used herein,denotes inhibitors of the serine protease thrombin. By inhibitingthrombin, various thrombin-mediated processes, such as thrombin-mediatedplatelet activation (that is, for example, the aggregation of platelets,and/or the secretion of platelet granule contents including serotonin)and/or fibrin formation are disrupted. A number of thrombin inhibitorsare known to one of skill in the art and these inhibitors arecontemplated to be used in combination with the present compounds. Suchinhibitors include, but are not limited to, boroarginine derivatives,boropeptides, heparins, hirudin, argatroban, dabigatran, AZD-0837, andthose disclosed in WO 98/37075 and WO 02/044145, and pharmaceuticallyacceptable salts and prodrugs thereof. Boroarginine derivatives andboropeptides include N-acetyl and peptide derivatives of boronic acid,such as C-terminal a-aminoboronic acid derivatives of lysine, omithine,arginine, homoarginine and corresponding isothiouronium analogs thereof.The term hirudin, as used herein, includes suitable derivatives oranalogs of hirudin, referred to herein as hirulogs, such asdisulfatohirudin.

The term thrombolytic (or fibrinolytic) agents (or thrombolytics orfibrinolytics), as used herein, denotes agents that lyse blood clots(thrombi). Such agents include tissue plasminogen activator (TPA,natural or recombinant) and modified forms thereof, anistreplase,urokinase, streptokinase, tenecteplase (TNK), lanoteplase (nPA), factorVIIa inhibitors, thrombin inhibitors, inhibitors of factors IXa, Xa, andXIa, PAI-I inhibitors (i.e., inactivators of tissue plasminogenactivator inhibitors), inhibitors of activated TAFI, alpha-2-antiplasmininhibitors, and anisoylated plasminogen streptokinase activator complex,including pharmaceutically acceptable salts or prodrugs thereof. Theterm anistreplase, as used herein, refers to anisoylated plasminogenstreptokinase activator complex, as described, for example, in EuropeanPatent Application No. 028,489, the disclosure of which is herebyincorporated herein by reference herein. The term urokinase, as usedherein, is intended to denote both dual and single chain urokinase, thelatter also being referred to herein as prourokinase.

Examples of suitable cholesterol/lipid lowering agents and lipid profiletherapies for use in combination with the compounds of the presentinvention include HMG-CoA reductase inhibitors (e.g., pravastatin,lovastatin, simvastatin, fluvastatin, atorvastatin, rosuvastatin, andother statins), low-density lipoprotein (LDL) receptor activitymodulators (e.g., HOE-402, PCSK9 inhibitors), bile acid sequestrants(e.g., cholestyramine and colestipol), nicotinic acid or derivativesthereof (e.g., NIASPAN®), GPR109B (nicotinic acid receptor) modulators,fenofibric acid derivatives (e.g., gemfibrozil, clofibrate, fenofibrateand benzafibrate) and other peroxisome proliferator-activated receptors(PPAR) alpha modulators, PPARdelta modulators (e.g., GW-501516),PPARgamma modulators (e.g., rosiglitazone), compounds that have multiplefunctionality for modulating the activities of various combinations ofPPARalpha, PPARgamma and PPARdelta, probucol or derivatives thereof(e.g., AGI-1067), cholesterol absorption inhibitors and/or Niemann-PickC1-like transporter inhibitors (e.g., ezetimibe), cholesterol estertransfer protein inhibitors (e.g., CP-529414), squalene synthaseinhibitors and/or squalene epoxidase inhibitors or mixtures thereof,acyl coenzyme A: cholesteryl acyltransferase (ACAT) 1 inhibitors, ACAT2inhibitors, dual ACAT1/2 inhibitors, ileal bile acid transportinhibitors (or apical sodium co-dependent bile acid transportinhibitors), microsomal triglyceride transfer protein inhibitors,liver-X-receptor (LXR) alpha modulators, LXRbeta modulators, LXR dualalpha/beta modulators, FXR modulators, omega 3 fatty acids (e.g.,3-PUFA), plant stanols and/or fatty acid esters of plant stanols (e.g.,sitostanol ester used in BENECOL® margarine), endothelial lipaseinhibitors, and HDL functional mimetics which activate reversecholesterol transport (e.g., apoAI derivatives or apoAI peptidemimetics).

The compounds of the present invention can also be combined with solubleguanylate cyclase inhibitors, Chymase inhibitors, ROMK inhibitors, ACEinhibitors, ATII inhibitors, ATR inhibitors, NEP inhibitors and othercompounds to treat heart failure.

The compounds of the present invention are also useful as standard orreference compounds, for example as a quality standard or control, intests or assays involving the inhibition of thrombin, Factor VIIa, IXa,Xa, XIa, and/or plasma kallikrein. Such compounds may be provided in acommercial kit, for example, for use in pharmaceutical researchinvolving thrombin, Factor VIIa, IXa, Xa, XIa, and/or plasma kallikrein.XIa. For example, a compound of the present invention could be used as areference in an assay to compare its known activity to a compound withan unknown activity. This would ensure the experimentor that the assaywas being performed properly and provide a basis for comparison,especially if the test compound was a derivative of the referencecompound. When developing new assays or protocols, compounds accordingto the present invention could be used to test their effectiveness.

The compounds of the present invention may also be used in diagnosticassays involving thrombin, Factor VIIa, IXa, Xa, XIa, and/or plasmakallikrein. For example, the presence of thrombin, Factor VIIa, IXa, XaXIa, and/or plasma kallikrein in an unknown sample could be determinedby addition of the relevant chromogenic substrate, for example S2366 forFactor XIa, to a series of solutions containing test sample andoptionally one of the compounds of the present invention. If productionof pNA is observed in the solutions containing test sample, but not inthe presence of a compound of the present invention, then one wouldconclude Factor XIa was present.

Extremely potent and selective compounds of the present invention, thosehaving K_(i) values less than or equal to 0.001 μM against the targetprotease and greater than or equal to 0.1 μM against the otherproteases, may also be used in diagnostic assays involving thequantitation of thrombin, Factor VIIa, IXa, Xa, XIa, and/or plasmakallikrein in serum samples. For example, the amount of Factor XIa inserum samples could be determined by careful titration of proteaseactivity in the presence of the relevant chromogenic substrate, S2366,with a potent Factor XIa inhibitor of the present invention.

The present invention also encompasses an article of manufacture. Asused herein, article of manufacture is intended to include, but not belimited to, kits and packages. The article of manufacture of the presentinvention, comprises: (a) a first container; (b) a pharmaceuticalcomposition located within the first container, wherein the composition,comprises: a first therapeutic agent, comprising: a compound of thepresent invention or a pharmaceutically acceptable salt form thereof;and, (c) a package insert stating that the pharmaceutical compositioncan be used for the treatment of a thromboembolic and/or inflammatorydisorder (as defined previously). In another embodiment, the packageinsert states that the pharmaceutical composition can be used incombination (as defined previously) with a second therapeutic agent totreat a thromboembolic and/or inflammatory disorder. The article ofmanufacture can further comprise: (d) a second container, whereincomponents (a) and (b) are located within the second container andcomponent (c) is located within or outside of the second container.

Located within the first and second containers means that the respectivecontainer holds the item within its boundaries.

The first container is a receptacle used to hold a pharmaceuticalcomposition. This container can be for manufacturing, storing, shipping,and/or individual/bulk selling. First container is intended to cover abottle, jar, vial, flask, syringe, tube (e.g., for a cream preparation),or any other container used to manufacture, hold, store, or distribute apharmaceutical product.

The second container is one used to hold the first container and,optionally, the package insert. Examples of the second containerinclude, but are not limited to, boxes (e.g., cardboard or plastic),crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks.The package insert can be physically attached to the outside of thefirst container via tape, glue, staple, or another method of attachment,or it can rest inside the second container without any physical means ofattachment to the first container. Alternatively, the package insert islocated on the outside of the second container. When located on theoutside of the second container, it is preferable that the packageinsert is physically attached via tape, glue, staple, or another methodof attachment. Alternatively, it can be adjacent to or touching theoutside of the second container without being physically attached.

The package insert is a label, tag, marker, etc. that recitesinformation relating to the pharmaceutical composition located withinthe first container. The information recited will usually be determinedby the regulatory agency governing the area in which the article ofmanufacture is to be sold (e.g., the United States Food and DrugAdministration). Preferably, the package insert specifically recites theindications for which the pharmaceutical composition has been approved.The package insert may be made of any material on which a person canread information contained therein or thereon. Preferably, the packageinsert is a printable material (e.g., paper, plastic, cardboard, foil,adhesive-backed paper or plastic, etc.) on which the desired informationhas been formed (e.g., printed or applied).

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments that are given forillustration of the invention and are not intended to be limitingthereof. The following Examples have been prepared, isolated andcharacterized using the methods disclosed herein.

VI. General Synthesis Including Schemes

The compounds of the present invention may be synthesized by manymethods available to those skilled in the art of organic chemistry(Maffrand, J. P. et al., Heterocycles, 16(1):35-37 (1981)). Generalsynthetic schemes for preparing compounds of the present invention aredescribed below. These schemes are illustrative and are not meant tolimit the possible techniques one skilled in the art may use to preparethe compounds disclosed herein. Different methods to prepare thecompounds of the present invention will be evident to those skilled inthe art. Additionally, the various steps in the synthesis may beperformed in an alternate sequence in order to give the desired compoundor compounds.

Examples of compounds of the present invention prepared by methodsdescribed in the general schemes are given in the intermediates andexamples section set out hereinafter. Preparation of homochiral examplesmay be carried out by techniques known to one skilled in the art. Forexample, homochiral compounds may be prepared by separation of racemicproducts by chiral phase preparative HPLC. Alternatively, the examplecompounds may be prepared by methods known to give enantiomericallyenriched products. These include, but are not limited to, theincorporation of chiral auxiliary functionalities into racemicintermediates which serve to control the diastereoselectivity oftransformations, providing enantio-enriched products upon cleavage ofthe chiral auxiliary.

The compounds of the present invention can be prepared in a number ofways known to one skilled in the art of organic synthesis. The compoundsof the present invention can be synthesized using the methods describedbelow, together with synthetic methods known in the art of syntheticorganic chemistry, or by variations thereon as appreciated by thoseskilled in the art. Preferred methods include, but are not limited to,those described below. The reactions are performed in a solvent orsolvent mixture appropriate to the reagents and materials employed andsuitable for the transformations being effected. It will be understoodby those skilled in the art of organic synthesis that the functionalitypresent on the molecule should be consistent with the transformationsproposed. This will sometimes require a judgment to modify the order ofthe synthetic steps or to select one particular process scheme overanother in order to obtain a desired compound of the invention.

It will also be recognized that another major consideration in theplanning of any synthetic route in this field is the judicious choice ofthe protecting group used for protection of the reactive functionalgroups present in the compounds described in this invention. Anauthoritative account describing the many alternatives to the trainedpractitioner is Greene et al. (Protective Groups in Organic Synthesis,Fourth Edition, Wiley-Interscience (2006)).

Representative compounds of this invention where ring A is a 6-memberedheterocycle (example—pyridine) can be derived from intermediates 1h, thesynthesis of which is described in Scheme 1. Condensation of aldehyde 1aprepared according to a modified procedure described by Negi (Synthesis,991 (1996)), with (S)-2-methylpropane-2-sulfinamide in the presence ofanhydrous copper sulfate or cesium carbonate in a solvent such as DCMgives the sulfinimine 1b (Ellman, J., J. Org. Chem., 64:1278 (1999)).Using a modified procedure described by Kuduk (Tetrahedron Letters,45:6641 (2004)), suitably substituted Grignard reagents, for exampleallylmagnesium bromide, can be added to sulfinimine 1b to give asulfinamide 1c, as a mixture of diastereomers which can be separated atvarious stages of the sequence. The diastereoselectivity for theaddition of allylmagnesium bromide to sulfinimine 1b can be improved byemploying indium(III) chloride according to a modified procedure of Xu(Xu, M.-H., Organic Letters, 10(6): 1259 (2008)). Protecting groupinterconversion can be accomplished in two steps to give 1d. Thischloropyridine can be coupled to 4-nitropyrazoles upon heating with a PdII salt such as Pd(OAc)₂ in the presence of a phosphine ligand and abase such as potassium carbonate in a solvent such as DMF or DMA in amicrowave reactor, as described by Sames (Goikhman, R. et al., J. Am.Chem. Soc., 131:3042 (2009)). Zinc/HOAc reduction of the nitropyrazolefollowed by amidation with an appropriately substituted carboxylic acidprovides 1f. Macrocyclization is then accomplished via ring-closingmetathesis using the Grubb's second generation ruthenium catalyst toyield 1g. Hydrogenation of the resulting olefin and protecting groupcleavage yields amine 1h. Compounds of the formulae 1h can be convertedto compounds in this invention according to Schemes 2 and 3.

Representative compounds of this invention can be prepared as shown inScheme 2. Starting from aldehyde 2a, vinyl Grignard addition (yieldingallylic alcohol 2b) followed by oxidation gives vinyl ketones 2c.Michael addition of the amines from Scheme 1 followed by acylation with2d affords compounds 2e, which upon cyclization with base provides thedihydropyridone 2f.

Compounds in this invention bearing alternate regiochemical pyrazolesubstitution can be synthesized as shown in Scheme 3. When R is anappropriate protective group (example—trimethylsilylethoxymethyl),deprotection of 3a to 3b can be followed by alkylation with an alkylhalide under basic conditions or upon reaction with a boronic acid inthe presence of Cu(II) salts such as Cu(OAc)₂. In most cases, thealkylation proceeds to give solely the product shown in 3c. In selectcases, products of the type shown in Scheme 2 are formed as a minorcomponent.

Representative pyridazinone compounds of this invention can be preparedas shown in Scheme 4. Using a modified procedure described by Vidal(Chem. Eur. J., 3(10):1691 (1997)), amine 1h can be reacted withoxaziridine 4a to give the Boc-protected hydrazine derivative.Deprotection with either TFA in dichloromethane or 4M HCl in dioxaneaffords hydrazine 4b. Condensation of hydrazine 4b and a suitablysubstituted hydroxy furanone 4c in methanol at elevated temperaturesprovides the pyridazinone 4d. Suitably substituted hydroxy furanonederivatives 4c can be prepared in two steps from styrene 4f according toa modified procedure described by van Niel (J. Med. Chem., 48:6004(2005)). Styrene 4f can be oxidized with lead tetraacetate in TFA togive the corresponding acetaldehyde derivative followed by condensationwith glyoxylic acid in the presence of morpholine and hydrochloric acidat elevated temperatures will provide 4c.

Intermediates for preparation of compounds of the present inventionwherein R² is —F can be prepared according to Scheme 5. Olefin 1g can besubjected to hydrofluorination, yielding as many as four isomeric alkylfluorides. Following separation of the isomers, deprotection of theamine protecting group is accomplished by the action of either TFA orHCl, as previously shown in Scheme 1. The intermediate 5a can beelaborated to compounds of this invention according to the proceduredescribed in Scheme 2.

Intermediates for preparation of compounds of the present inventionwherein R² is —F can be prepared according to Scheme 5. Olefin 1g can besubjected to hydrofluorination, yielding as many as four isomeric alkylfluorides. Following separation of the isomers, deprotection of theamine protecting group is accomplished by the action of either TFA orHCl, as previously shown in Scheme 1. The intermediate 5a can beelaborated to compounds of this invention according to the proceduredescribed in Scheme 2.

Compounds in this invention with pyridone connected to the macrocycle(6a) can be synthesized by oxidation of compounds 2f with variousoxidations conditions such as CuI in DMSO, or cumenehydroperoxide/Pealman's catalyst as shown in Scheme 6.

Alternatively, compounds in this invention (6a) with pyridone connectedto the macrocycle can be synthesized as shown in Scheme 7. Treatment of1-ethoxyprop-1-ene with malonyl dichloride followed by quenching withethanol provides compound 7a, which can be hydrolyzed to 7b withKOH/EtOH. 7b can be subjected to concentrated H₂SO₄ at high temperatureto provide 7c, which can react with 1h to give 7d. 7d can be convertedto its triflate 7e, and upon Suzuki coupling with various boronic acid,compounds of this invention 6a can be prepared.

Intermediate 1 Preparation of1-(3-chloro-2,6-difluorophenyl)prop-2-en-1-one

1A. Preparation of 1-(3-chloro-2,6-difluorophenyl)prop-2-en-1-ol

To a 100 mL dry RBF containing 1 M vinylmagnesium bromide in THF (24 mL,24.0 mmol) under Ar at 0° C. was added 3-chloro-2,6-difluorobenzaldehyde(3.2 g, 18.13 mmol) in THF (10 mL) dropwise. The reaction was stirredfor 1 h and quenched with 1 N HCl to pH 2. The mixture was extractedwith Et₂O (3×). The combined organic layer was washed with brine, driedover MgSO₄, filtered, and concentrated to yield1-(3-chloro-2,6-difluorophenyl)prop-2-en-1-ol (3.71 g, 100%) as a paleyellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.34 (ddd, J=8.9, 8.1, 5.8 Hz,1H), 6.90 (td, J=9.2, 1.7 Hz, 1H), 6.23 (dddt, J=17.2, 10.4, 5.8, 1.2Hz, 1H), 5.60 (dd, J=7.6, 6.7 Hz, 1H), 5.40-5.31 (m, 1H), 5.28 (dt,J=10.2, 1.2 Hz, 1H), 2.38 (dt, J=8.3, 1.9 Hz, 1H).

1B. Preparation of 1-(3-chloro-2,6-difluorophenyl)prop-2-en-1-one

To a solution of 1-(3-chloro-2,6-difluorophenyl)prop-2-en-1-ol (3.7 g,18.08 mmol) in acetone (90 mL) at 0° C. was added Jones reagent (8.77ml, 23.51 mmol) dropwise. Upon finishing addition of Jones reagent, thereaction was quenched with iPrOH. The mixture was concentrated. Theresidue was suspended in water and extracted with DCM (3×). The combinedorganic layer was washed with brine, dried over MgSO₄, filtered, andconcentrated. The residue was purified by silica gel chromatography toyield 1-(3-chloro-2,6-difluorophenyl)prop-2-en-1-one as a yellow oil(3.45 g, 94%) which solidified in freezer. ¹H NMR (500 MHz, CDCl₃) δ7.48 (ddd, J=9.0, 8.0, 5.5 Hz, 1H), 7.05-6.91 (m, 1H), 6.70 (ddt,J=17.5, 10.5, 1.1 Hz, 1H), 6.29-6.11 (m, 2H).

Intermediate 2 Preparation of1-(3-chloro-2-fluoro-6-(trifluoromethyl)phenyl)prop-2-en-1-one

1-(3-Chloro-2-fluoro-6-(trifluoromethyl)phenyl)prop-2-en-1-one wasprepared using a procedure analogous to that used for the preparation ofIntermediate 1 by replacing 3-chloro-2,6-difluorobenzaldehyde with3-chloro-2-fluoro-6-(trifluoromethyl) benzaldehyde. ¹H NMR (500 MHz,CDCl₃) δ 7.64 (ddd, J=8.0, 7.4, 0.8 Hz, 1H), 7.50 (dd, J=8.5, 0.6 Hz,1H), 6.69 (dd, J=17.6, 10.7 Hz, 1H), 6.27 (d, J=10.7 Hz, 1H), 6.01 (dd,J=17.7, 0.7 Hz, 1H).

Intermediate 3 Preparation of1-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one

3A. Preparation of 5-chloro-2-(1H-1,2,3-triazol-1-yl)benzaldehyde

A septum cap-sealed vial was charged with 5-chloro-2-fluorobenzaldehyde(1.0 g, 6.31 mmol), 1H-1,2,3-triazole (3.0 g, 43.4 mmol), and Cs₂CO₃(2.260 g, 6.94 mmol). The thick solution was heated at 90° C. for 1 h.Purification by silica gel chromatography yielded a mixture of thedesired product and unreacted triazole starting material. Upon additionof ˜5-10 mL water, the product precipitated. Filtration and drying invacuo yielded 5-chloro-2-(1H-1,2,3-triazol-1-yl)benzaldehyde as a whitesolid (0.52 g, 40%). MS(ESI) m/z: 208.3 (M+H)⁺. ¹H NMR (500 MHz, CDCl₃)δ 9.85 (s, 1H), 8.09 (d, J=2.2 Hz, 1H), 7.97 (d, J=1.1 Hz, 1H), 7.94 (d,J=0.8 Hz, 1H), 7.73 (dd, J=8.4, 2.3 Hz, 1H), 7.49 (d, J=8.3 Hz, 1H).

3B. Preparation of1-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one

1-(5-Chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one was preparedusing a procedure analogous to that used for the preparation ofIntermediate 1 by using 5-chloro-2-(1H-1,2,3-triazol-1-yl)benzaldehyde.MS(ESI) m/z: 234.3 (M+H)⁺. ¹H NMR (500 MHz, CDCl₃) δ 7.82-7.78 (m, 2H),7.66-7.59 (m, 2H), 7.56-7.51 (m, 1H), 6.25 (dd, J=17.6, 10.7 Hz, 1H),5.93 (dd, J=17.3, 0.6 Hz, 1H), 5.82 (dd, J=10.7, 0.6 Hz, 1H).

Intermediate 4 Preparation of1-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one

4A. Preparation of 2-azido-5-chlorobenzaldehyde

A solution of 5-chloro-2-fluorobenzaldehyde (1.38 g, 8.70 mmol) and NaN₃(0.58 g, 8.92 mmol) in DMF (4 mL) was stirred at 55° C. for 8 h thencooled to rt. The reaction mixture was diluted with Et₂O and water whichwas then acidified with 1 N HCl to pH 4. The organic layer was washedwith water (3×) followed by brine (3×), then dried over MgSO₄ andfiltered. The organic layers were then concentrated to yield 1.47 g of2-azido-5-chlorobenzaldehyde (93%) as pale yellow solid. ¹H NMR (400MHz, CDCl₃-d) δ 10.30 (s, 1H), 7.86 (d, J=2.6 Hz, 1H), 7.58 (dd, J=8.7,2.5 Hz, 1H), 7.24 (d, J=8.6 Hz, 1H).

4B. Preparation of5-chloro-2-(4-(tributylstannyl)-1H-1,2,3-triazol-1-yl)benzaldehyde

A solution of 2-azido-5-chlorobenzaldehyde (386 mg, 2.126 mmol) andtributylstanylacetylene (0.646 mL, 2.126 mmol) in toluene (5 mL) washeated at 100° C. for 5 h then cooled to rt. After 5 h, the reactionmixture was concentrated and directly purified using normal phasechromatography to yield 495 mg of5-chloro-2-(4-(tributylstannyl)-1H-1,2,3-triazol-1-yl)benzaldehyde (43%)as pale yellow oil. MS(ESI) m/z: 498.1 (M+H)⁺.

4C. Preparation of5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)benzaldehyde

To a solution of5-chloro-2-(4-(tributylstannyl)-1H-1,2,3-triazol-1-yl)benzaldehyde (459mg, 0.924 mmol) in ACN (5 mL) was added NCS (185 mg, 1.386 mmol) and thereaction was then heated at 60° C. for 15 h. After 15 h, the reactionmixture was concentrated and directly purified using normal phasechromatography to yield 117 mg of5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)benzaldehyde (52%) as whitesolid. MS(ESI) m/z: 242.0 (M+H, chlorine isotope peak)⁺.

4D. Preparation of1-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one

1-(5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one wasprepared using a procedure analogous to that used for the preparation ofIntermediate 1 by replacing 3-chloro-2,6-difluorobenzaldehyde with5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)benzaldehyde. MS(ESI) m/z:268.3 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.71-7.66 (m, 1H), 7.62-7.52 (m,2H), 7.44 (d, J=8.4 Hz, 1H), 6.29 (dd, J=17.6, 10.6 Hz, 1H), 5.98-5.79(m, 2H).

Intermediate 5 Preparation of diethyl (2-chloro-2-oxoethyl)phosphonate

To a solution of 2-(diethoxyphosphoryl)acetic acid (0.1 mL, 0.622 mmol)in CH₂Cl₂ (1 mL) was added 2 M (CO)₂Cl₂ in DCM (0.6 mL, 1.24 mmol),followed by a drop of DMF. The reaction was stirred at rt for 2.5 h andconcentrated in vacuo to yield diethyl (2-chloro-2-oxoethyl)phosphonateas yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 4.24 (dq, J=8.4, 7.1 Hz, 4H),3.55-3.47 (d, J=21.46 Hz, 2H), 1.42-1.38 (t, J=7.4 Hz, 6H).

Intermediate 6 Preparation of (R)-2-methylbut-3-enoic acid

6A. Preparation of(R)-4-benzyl-3-((R)-2-methylbut-3-enoyl)oxazolidin-2-one

To the solution of 2-methylbut-3-enoic acid (5.59 g, 55.9 mmol) and NMM(6.14 ml, 55.9 mmol) in THF (62 mL) at 0° C. was added pivaloyl chloride(6.87 ml, 55.9 mmol) dropwise. The reaction mixture was cooled to −78°C., and stirred for ˜2 h. In a separate flask: To the solution of(R)-4-benzyloxazolidin-2-one (8.25 g, 46.6 mmol) in THF (126 mL) at −78°C. was added 2.5 M nBuLi in hexane (20.49 mL, 51.2 mmol) dropwise. After35 min, this reaction was transferred via cannula to the first reaction.The reaction mixture was stirred at −78° C. for 2 h, then the cold bathwas removed, and the reaction was quenched with sat NH₄Cl. The reactionwas diluted with water and extracted with EtOAc (3×). The combinedorganic layers were washed with brine, dried over Na₂SO₄, filtered, andconcentrated to give a yellow oil (15 g). Purification by silica gelchromatography afforded(R)-4-benzyl-3-((R)-2-methylbut-3-enoyl)oxazolidin-2-one (6.59 g, 55%)as a colorless oil. MS(ESI) m/z: 282.1 (M+Na)⁺. ¹H NMR (500 MHz, CDCl₃)δ 7.36-7.19 (m, 5H), 6.03-5.93 (m, 1H), 5.23-5.10 (m, 2H), 4.69-4.63 (m,1H), 4.51-4.43 (m, 1H), 4.23-4.15 (m, 2H), 3.29 (dd, J=13.5, 3.3 Hz,1H), 2.79 (dd, J=13.5, 9.6 Hz, 1H), 1.35 (d, J=6.9 Hz, 3H) ppm. Theother diastereomer(R)-4-benzyl-3-((S)-2-methylbut-3-enoyl)oxazolidin-2-one (4.6 g, 38%)also was obtained as a white solid. MS(ESI) m/z: 260.1 (M+H)⁺.

6B. Preparation of (R)-2-methylbut-3-enoic acid

To a clear colorless solution of(R)-4-benzyl-3-((R)-2-methylbut-3-enoyl) oxazolidin-2-one (6.05 g, 23.33mmol) in THF (146 mL) at 0° C. was added with CHCl₃ (3×). The aqueouslayer was acidified with conc. HCl to pH-3 and then it was extractedwith EtOAc (3×). The EtOAc layers were combined, washed with brine,dried over MgSO₄, filtered and concentrated to afford(R)-2-methylbut-3-enoic acid (2.15 g, 92%) as a colorless oil. ¹H NMR(500 MHz, CDCl₃) δ 10.84 (br. s., 1H), 5.94 (ddd, J=17.4, 10.1, 7.4 Hz,1H), 5.22-5.13 (m, 2H), 3.23-3.15 (m, 1H), 1.31 (d, J=7.2 Hz, 3H).

Intermediate 7 Preparation of 1-cyclopropyl-4-nitro-1H-pyrazole

DCE (66 ml) was added to 4-nitro-1H-pyrazole (1.5 g, 13.3 mmol),cyclopropylboronic acid (2.28 g, 26.5 mmol), 2,2′-bipyridine (2.1 g,13.3 mmol), and Na₂CO₃ (2.81 g, 26.5 mmol) in a 250 mL RBF. It waspurged with Ar (3×). Cu(OAc)₂ (2.41 g, 13.3 mmol) was added followedpurging with Ar. The reaction was then heated under Ar for 6 h. Upon thecompletion of reaction, the mixture was filtered through CELITE® andconcentrated. Purification with silica gel chromatography yielded1-cyclopropyl-4-nitro-1H-pyrazole (0.965 g, 47.5%) as a white solid.

Intermediate 8 Preparation of 1-ethyl-4-nitro-1H-pyrazole

1-Ethyl-4-nitro-1H-pyrazole was prepared in the same manner as that usedfor the preparation of 1-methyl-4-nitro-1H-pyrazole described in Example1D, by substituting EtI for MeI.

Intermediate 9 Preparation of 1-(2,2-difluoroethyl)-4-nitro-1H-pyrazole

1-(2,2-Difluoroethyl)-4-nitro-1H-pyrazole was prepared in the samemanner as that used for the preparation of 1-methyl-4-nitro-1H-pyrazoledescribed in Example 1D by substituting 2,2-difluoroethyltrifluoromethanesulfonate for MeI. ¹H NMR (400 MHz, CDCl₃) δ 8.24 (s,1H), 8.13 (s, 1H), 6.34-5.97 (m, 1H), 4.52 (td, J=13.5, 4.1 Hz, 2H).

Intermediate 10 Preparation of4-nitro-1-(2,2,2-trifluoroethyl)-1H-pyrazole

4-Nitro-1-(2,2,2-trifluoroethyl)-1H-pyrazole was prepared in the samemanner as that used for the preparation of 1-methyl-4-nitro-1H-pyrazoledescribed in Example 1D by replacing 1,1,1-trifluoro-3-iodopropane forMeI. ¹H NMR (400 MHz, CDCl₃) δ 8.30 (s, 1H), 8.16 (s, 1H), 4.77 (q,J=8.1 Hz, 2H).

Intermediate 11 Preparation of4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

4-Nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole was prepared inthe same manner as that used for the preparation of1-methyl-4-nitro-1H-pyrazole described in Example 1D by substitutingSEM-Cl for MeI. ¹H NMR (400 MHz, CDCl₃) δ 8.30 (s, 1H), 8.10 (s, 1H),5.45 (s, 2H), 3.63 (dd, J=8.9, 7.8 Hz, 3H), 0.98-0.90 (m, 3H),0.02-−0.02 (m, 10H).

Intermediate 12 Preparation of1-(6-bromo-3-chloro-2-fluorophenyl)prop-2-en-1-one

1-(6-Bromo-3-chloro-2-fluorophenyl)prop-2-en-1-one was prepared using aprocedure analogous to intermediate 1 by replacing3-chloro-2,6-difluorobenzaldehyde with6-bromo-3-chloro-2-fluorobenzaldehyde. ¹H NMR (500 MHz, CDCl₃) δ7.33-7.41 (m, 2H), 6.64 (dd, J=17.6, 10.2 Hz, 1H), 6.25 (d, J=10.7 Hz,1H), 6.07 (d, J=17.6 Hz, 1H).

Intermediate 13 Preparation of 1-(2-bromo-5-chlorophenyl)prop-2-en-1-one

Intermediate 13 was prepared from 2-bromo-5-chlorobenzaldehyde usingmethods described for the synthesis of Intermediate 1 from3-chloro-2,6-difluorobenzaldehyde to yield1-(2-bromo-5-chlorophenyl)prop-2-en-1-one (1.4 g, 97%) as a clear,colorless oil. ¹H NMR (500 MHz, CDCl₃) δ 7.97 (dd, J=8.5, 1.4 Hz, 1H),7.79-7.65 (m, 2H), 7.19-7.06 (m, 1H), 6.61-6.48 (m, 2H).

Intermediate 14 Preparation of 1-(difluoromethyl)-4-nitro-1H-pyrazole

Cs₂CO₃ (14.41 g, 44.2 mmol) was suspended in a solution of4-nitro-1H-pyrazole (5.00 g, 44.2 mmol) and DMF (40 mL). After heatingto 120° C. for 5 min, solid sodium 2-chloro-2,2-difluoroacetate (13.48g, 88 mmol) was added in 10 equal portions over 20 min. The reaction wascomplete after 10 min of additional heating. The mixture was added to aseparatory funnel containing 100 mL water and extracted with Et₂O (2×50mL). The combined organic layers were concentrated. Purification bynormal-phase chromatography eluting with a gradient of hexanes/EtOAcyielded 1-(difluoromethyl)-4-nitro-1H-pyrazole (6.99 g, 42.9 mmol, 97%yield) as a clear, colorless oil. ¹H NMR (500 MHz, CDCl₃) δ 8.58 (s,1H), 8.22 (s, 1H), 7.39-7.05 (t, J=60 Hz, 1H).

Intermediate 15 Preparation of1-(2,2-difluorocyclopropyl)-4-nitro-1H-pyrazole

15A. Preparation of 4-nitro-1-vinyl-1H-pyrazole

4-Nitro-1H-pyrazole (1 g, 8.84 mmol) and BTEAC (0.20 g, 0.884 mmol) wereadded to a vial containing DCE (5 mL) and 50% aq NaOH (3.5 g, 44.2mmol). The reaction was heated to 80° C. for 6 h. The reaction wasfiltered, the filtrate was concentrated to dryness in vacuo, and theresidue was purified with normal phase chromatography (hexanes-EtOAcgradient). 4-Nitro-1-vinyl-1H-pyrazole (0.87 g, 71% yield) was isolatedas a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.31 (s, 1H), 8.16 (s, 1H),7.02 (dd, J=15.6, 8.8 Hz, 1H), 5.80 (dd, J=15.5, 1.9 Hz, 1H), 5.17 (dd,J=8.8, 2.0 Hz, 1H).

15B. Preparation of 1-(2,2-difluorocyclopropyl)-4-nitro-1H-pyrazole

Trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.57 mL, 2.88mmol) was slowly dropped (over 20 min) into a mixture of4-nitro-1-vinyl-1H-pyrazole (0.2 g, 1.44 mmol) and NaF (6 mg, 0.144mmol) in methyl benzoate (1 mL), and the solution was heated to 105° C.Upon completion of the addition, the reaction was complete. The mixturewas cooled to rt and subjected directly to normal phase chromatography(hexanes-EtOAc gradient) to yield1-(2,2-difluorocyclopropyl)-4-nitro-1H-pyrazole (0.084 g, 30.9% yield)as a yellow, crystalline solid. ¹H NMR (400 MHz, CDCl₃) δ 8.26 (s, 1H),8.12 (s, 1H), 4.18 (dddd, J=10.4, 8.4, 6.2, 2.3 Hz, 1H), 2.40-2.10 (m,2H).

Intermediate 16 Preparation of1-(3-chloro-6-(difluoromethoxy)-2-fluorophenyl)prop-2-en-1-one

16A. Preparation of 3-chloro-6-(difluoromethoxy)-2-fluorobenzaldehyde

To a solution of 1-chloro-4-(difluoromethoxy)-2-fluorobenzene (400 mg,2.04 mmol) in THF (8 mL) at −78° C. was added LDA inTHF/heptane/ethylbenzene (1.4 mL, 2.4 mmol) dropwise. After continuingto stir at the same temp for 20 min, DMF (0.2 mL, 2.44 mmol) was addedin one portion and stirring was continued at the same temperature for 10min. HOAc (0.47 mL, 8.14 mmol) was added followed by water (30 mL). Theaqueous layer was then extracted with EtOAc. The combined organic layerswere dried over MgSO₄ and concentrated in vacuo. The crude product waspurified by normal phase chromatography to yield3-chloro-6-(difluoromethoxy)-2-fluorobenzaldehyde (120 mg, 21%) as aclear, colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 10.35 (d, J=0.9 Hz, 1H),7.63 (dd, J=8.9, 8.0 Hz, 1H), 7.07 (dd, J=8.9, 1.2 Hz, 1H), 6.87-6.39(t, J=72 Hz, 1H).

16B. Preparation of1-(3-chloro-6-(difluoromethoxy)-2-fluorophenyl)prop-2-en-1-one

1-(3-Chloro-6-(difluoromethoxy)-2-fluorophenyl)prop-2-en-1-one wasprepared from 3-chloro-6-(difluoromethoxy)-2-fluorobenzaldehyde usingmethods described for the synthesis of Intermediate 1 from3-chloro-2,6-difluorobenzaldehyde to yield3-chloro-6-(difluoromethoxy)-2-fluorobenzaldehyde (0.04 g, 67% yield) asa clear, colorless oil. ¹H NMR (500 MHz, CDCl₃) δ 7.48 (dd, J=8.9, 8.1Hz, 1H), 7.08-7.01 (m, 1H), 6.69-6.63 (m, 1H), 6.63-6.30 (t, J=73 Hz,1H), 6.18 (d, J=10.5 Hz, 1H), 6.10 (d, J=17.6 Hz, 1H).

Intermediate 17 Preparation of13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

17A. Preparation of13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

13-{4-[5-Chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onewas prepared according to the procedures described in Example 1 bysubstituting 1-methyl-4-nitro-1H-pyrazole with4-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole, Intermediate11.

17B. Preparation of13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

13-{4-[5-Chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-9-methyl-3-{[2-(trimethylsilyl)ethoxy]methyl}-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onewas immediately treated with HCl to yield13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one.¹H NMR (500 MHz, CD₃OD) δ 8.69-8.64 (m, 1H), 8.36-8.32 (m, 1H),7.94-7.90 (m, 2H), 7.82-7.77 (m, 2H), 7.65 (s, 2H), 7.62-7.58 (m, 1H),5.87-5.82 (m, 1H), 5.56-5.50 (m, 1H), 3.44-3.39 (m, 2H), 2.69-2.60 (m,1H), 2.30-2.11 (m, 3H), 2.10-1.93 (m, 2H), 1.74-1.65 (m, 1H), 1.42-1.28(m, 2H), 1.20-1.14 (m, 3H). MS(ESI) m/z: 543.6 (M+H)⁺. Analytical HPLC(Method A): RT=4.71 min, purity=>99.5%.

Intermediate 18 Preparation of(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,2,3,6-tetrahydropyridin-1-yl]-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-[4-(3-Chloro-2,6-difluorophenyl)-6-oxo-1,2,3,6-tetrahydropyridin-1-yl]-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onewas prepared in a manner similar to13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,Intermediate 17, by substituting1-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one with1-(3-chloro-2,6-difluorophenyl)prop-2-en-1-one to yield (0.5 mg, 11%)MS(ESI) m/z: 512.1 (M+H)⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.68-8.59 (m, 1H),7.82 (s, 1H), 7.78-7.70 (m, 1H), 7.59-7.50 (m, 2H), 7.18-7.05 (m, 1H),6.19-6.09 (m, 1H), 5.75-5.61 (m, 1H), 3.83-3.73 (m, 1H), 3.73-3.56 (m,2H), 2.82-2.59 (m, 3H), 2.26-2.14 (m, 1H), 2.13-2.03 (m, 1H), 2.03-1.93(m, 1H), 1.76-1.63 (m, 1H), 1.45-1.26 (m, 2H), 1.25-1.18 (m, 2H), 1.14(d, J=6.9 Hz, 5H). Analytical HPLC (Method A): RT=5.67 min, purity=100%.

Intermediate 19 Preparation of(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

19A. Preparation of 1-(difluoromethyl)-4-nitro-1H-pyrazole

Cs₂CO₃ (14.41 g, 44.2 mmol) was suspended in a solution of4-nitro-1H-pyrazole (5.00 g, 44.2 mmol) and DMF (40 mL). After heatingto 120° C. for 5 min, solid sodium 2-chloro-2,2-difluoroacetate (13.48g, 88 mmol) was added in 10 equal portions over 20 min. The reaction wascomplete after 10 min of additional heating. The mixture was added to aseparatory funnel containing 100 mL water and extracted with Et₂O (2×50mL). The combined organic layers were concentrated. Purification bynormal-phase chromatography eluting with a gradient of hexanes/EtOAcyielded 1-(difluoromethyl)-4-nitro-1H-pyrazole (6.99 g, 42.9 mmol, 97%yield) as a clear, colorless oil. ¹H NMR (500 MHz, CDCl₃) δ 8.58 (s,1H), 8.22 (s, 1H), 7.39-7.05 (t, J=60 Hz, 1H).

19B. Preparation of (S)-tert-butyl(1-(4-(1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate

To a N₂ flushed, 500 mL RBF was added (S)-tert-butyl(1-(4-chloropyridin-2-yl)but-3-en-1-yl)carbamate, prepared as describedin Example 1C, (10 g, 35.4 mmol),1-(difluoromethyl)-4-nitro-1H-pyrazole, Intermediate 14, (6.34 g, 38.9mmol) and dioxane (100 mL). The solution was bubbled with N₂ for 5 min.and Pd(OAc)₂ (0.40 g, 1.7 mmol), di(adamantan-1-yl)(butyl)phosphine(1.27 g, 3.5 mmol), K₂CO₃ (14.7 g, 106 mmol) and PvOH (1.08 g, 10.61mmol) were added. The reaction mixture was bubbled with N₂ for 5 min. Itwas then heated to 100° C. for 3 h. Water (200 mL) was added. Thereaction mixture was then extracted with EtOAc (2×200 mL). The combinedorganic extracts were washed with water (200 mL), brine (200 mL), driedover Na₂SO₄, filtered and concentrated in vacuo. Purification by normalphase chromatography eluting with a gradient of hexanes/EtOAc afforded(S)-tert-butyl(1-(4-(1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(12.91 g, 31.5 mmol, 89% yield) as a slightly yellow oil. MS(ESI) m/z:410.4 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.80 (dd, J=5.1, 0.7 Hz, 1H),8.36 (s, 1H), 7.34 (s, 1H), 7.31 (dd, J=5.1, 1.5 Hz, 1H), 7.27-6.91 (t,J=58 Hz, 1H), 5.79-5.63 (m, 1H), 5.16-5.03 (m, 2H), 4.92 (d, J=5.9 Hz,1H), 2.67 (t, J=6.4 Hz, 2H), 1.46 (br. s., 9H).

19C. Preparation of (S)-tert-butyl(1-(4-(4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate

To a 100 mL, 3-necked RBF was added a solution of (S)-tert-butyl(1-(4-(1-(difluoromethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(0.78 g, 1.90 mmol) in MeOH (12 mL) and a solution of NH₄Cl (1.02 g, 19mmol) in water (3 mL). To the solution was added Fe (0.53 g, 9.49 mmol).The reaction mixture was heated to 65° C. for 3 h. Water (50 mL) wasadded. After cooling to rt, the mixture was filtered through a CELITE®pad and rinsed with MeOH (200 mL). The filtrate was concentrated invacuo. The residue was partitioned between EtOAc (100 mL) and water (100mL). The organic phase was separated, washed with water (100 mL), brine(100 mL), dried over Na₂SO₄, filtered and concentrated in vacuo.Purification by normal phase chromatography eluting with a gradient ofDCM/MeOH yielded (S)-tert-butyl(1-(4-(4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(0.585 g, 1.54 mmol, 81% yield) as an oil. MS(ESI) m/z: 380.1 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.70 (dd, J=5.0, 0.7 Hz, 1H), 7.43 (s, 1H), 7.36(s, 1H), 7.32 (dd, J=5.1, 1.5 Hz, 1H), 7.28-6.97 (t, J=58 Hz, 1H),5.80-5.66 (m, 1H), 5.65-5.53 (m, 1H), 5.13-5.03 (m, 2H), 4.87 (br. s.,1H), 3.22 (br. s., 2H), 2.65 (t, J=6.5 Hz, 2H), 1.52-1.37 (m, 9H).

19D. Preparation of tert-butyl((S)-1-(4-(1-(difluoromethyl)-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate

To a N₂ flushed, 3-necked, 250 mL RBF was added a solution of(S)-tert-butyl(1-(4-(4-amino-1-(difluoromethyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(5 g, 13.18 mmol) and EtOAc (50 mL). The solution was cooled to −10° C.and (R)-2-methylbut-3-enoic acid, Intermediate 6, (1.72 g, 17.13 mmol),pyridine (4.26 mL, 52.7 mmol) and T3P® (23.54 mL, 39.5 mmol) were added.The cooling bath was removed and the solution was allowed to warm to rtand then stir over a period of 20 h. Water (30 mL) and EtOAc (30 mL)were added and the mixture was stirred for 30 min. The organic phase wasseparated and the aqueous layer was extracted with EtOAc (30 mL). Thecombined organic extracts were washed with brine (50 mL), dried overNa₂SO₄, filtered and concentrated in vacuo. Purification by normal phasechromatography eluting with a gradient of hexanes/EtOAc gave tert-butyl((5)-1-(4-(1-(difluoromethyl)-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(5.69 g, 12.33 mmol, 94% yield). MS(ESI) m/z: 462.2 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 8.75 (dd, J=5.0, 0.6 Hz, 1H), 8.37 (s, 1H), 7.32 (t, J=59Hz, 1H), 7.28 (br. s., 1H), 7.20 (s, 1H), 5.97-5.85 (m, 1H), 5.78-5.65(m, 1H), 5.56-5.44 (m, 1H), 5.28-5.19 (m, 2H), 5.12 (d, J=2.0 Hz, 2H),4.91-4.82 (m, 1H), 3.20-3.11 (m, 1H), 2.72-2.62 (m, 2H), 1.48-1.43 (s,9H), 1.33 (d, J=6.8 Hz, 3H).

19E. Preparation of tert-butylN-[(9R,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate

To a N₂ flushed, 2 L, 3-necked, RBF was added a solution of tert-butyl((S)-1-(4-(1-(difluoromethyl)-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(3 g, 6.50 mmol) in EtOAc (1300 mL). The solution was sparged with Arfor 15 mi. Second Generation Grubbs Catalyst (1.38 g, 1.63 mmol) wasadded in one portion. The reaction mixture was heated to reflux for 24h. After cooling to rt, the solvent was removed and the residue waspurified by normal phase chromatography eluting with a gradient ofDCM/MeOH to yield tert-butylN-[(9R,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(2.13 g, 4.91 mmol, 76% yield) as a tan solid. MS(ESI) m/z: 434.4[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.71 (d, J=5.1 Hz, 1H), 7.78 (s, 1H),7.44-7.40 (m, 1H), 7.36 (br. s., 1H), 7.27 (t, J=58 Hz, 1H), 6.87 (s,1H), 6.49-6.39 (m, 1H), 5.78 (s, 1H), 4.80 (br. s., 2H), 3.18-3.08 (m,1H), 3.08-2.98 (m, 1H), 2.06-1.93 (m, 1H), 1.51 (s, 9H), 1.19 (d, J=6.6Hz, 3H).

19F. Preparation of tert-butylN-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate

Pd on carbon (0.60 g, 0.570 mmol) was added to a 250 mL Parrhydrogenation flask containing a solution of tert-butylN-[(9R,10E,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(2.46 g, 5.68 mmol) in EtOH (100 mL). The flask was purged with N₂ andpressurized to 55 psi of H₂ allowed to stir for 18 h. The reaction wasfiltered through CELITE® and concentrated to yield tert-butylN-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(2.17 g, 88% yield) as a tan solid. MS(ESI) m/z: 436.3 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 9.32 (s, 1H), 8.71 (d, J=5.0 Hz, 1H), 7.96 (t, J=58Hz, 1H), 7.43 (s, 1H), 7.32 (d, J=4.8 Hz, 1H), 7.22 (d, J=7.3 Hz, 1H),4.66 (d, J=8.3 Hz, 1H), 2.62 (br. s., 1H), 1.88 (d, J=12.8 Hz, 1H),1.77-1.59 (m, 2H), 1.42-1.28 (m, 9H), 1.15 (d, J=18.2 Hz, 2H), 0.83 (d,J=7.0 Hz, 3H).

19G. Preparation of(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

4 N HCl in dioxane (3.88 mL, 15.5 mmol) was added to a solution oftert-butylN-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(2.25 g, 5.2 mmol) in MeOH (10 mL). The reaction was allowed to stir atrt for 2 h. The reaction was cooled in an ice bath, and 7 N NH₃ in MeOH(13.3 mL, 93.0 mmol) was added. After 5 min, the reaction was dilutedwith CH₂Cl₂ (80 mL) and the solid that formed was filtered. The filtratewas concentrated to yield(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(1.3 g, 3.88 mmol, 75% yield). MS(ESI) m/z: 336.3 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 9.33 (s, 1H), 8.71 (d, J=5.0 Hz, 1H), 7.94 (t, J=58 Hz,1H), 7.85 (s, 1H), 7.40 (s, 1H), 7.32 (d, J=5.0 Hz, 1H), 4.01 (dd,J=10.2, 5.1 Hz, 1H), 2.63-2.53 (m, 1H), 1.90-1.69 (m, 2H), 1.53-1.36 (m,2H), 1.16-1.00 (m, 1H), 0.85 (d, J=7.0 Hz, 3H).

Example 1 Preparation of(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

1A. Preparation of(S,E)-N-((4-chloropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide

To a solution of S-(−)-t-butyl-sulfinamide (0.856 g, 7.06 mmol) in DCM(14.13 mL) was added sequentially CuSO₄ (2.481 g, 15.54 mmol) and4-chloropicolinaldehyde (1.0 g, 7.06 mmol) The white suspension wasstirred at rt. After 3 h, the brown suspension was filtered throughCELITE®, eluting with DCM, to give a clear brown filtrate. Concentrationgave a brown oil weighing 1.85 g. Purification by normal phasechromatography gave 1.31 g of(S,E)-N-((4-chloropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamideas a clear, yellow oil. MS(ESI) m/z: 245.0 (M+H)⁺.

1B. Preparation of(S)—N—((S)-1-(4-chloropyridin-2-yl)but-3-enyl)-2-methylpropane-2-sulfinamide

To a cooled (0-5° C.) mixture of InCl₃ (13.56 g, 61.3 mmol) in THF (170mL) was added dropwise over 30 min a solution of 1 M allylmagnesiumbromide in Et₂O (62 mL, 61.3 mmol). The reaction was allowed to warm tort. After 1 h at rt, a solution of(S,E)-N-((4-chloropyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide(10 g, 40.9 mmol) in EtOH (170 mL) was added. After 2-3 h, the reactionwas concentrated under vacuum at 50-55° C. The crude material waspartitioned between EtOAc (200 ml) and water (50 ml) and the layers wereseparated. The aqueous layer was extracted with EtOAc (2×50 ml). Theorganic layers were combined and washed with brine (100 ml), dried overNa₂SO₄, filtered and concentrated to give(S)—N—((S)-1-(4-chloropyridin-2-yl)but-3-enyl)-2-methylpropane-2-sulfinamide(13.5 g, 106%) as a yellow oil. MS(ESI) m/z: 287.2 (M+H)⁺.

1C. Preparation of (S)-tert-butyl1-(4-chloropyridin-2-yl)but-3-enylcarbamate

(S)—N—((S)-1-(4-Chloropyridin-2-yl)but-3-enyl)-2-methylpropane-2-sulfinamide(75 g, 261 mmol) was dissolved in MeOH (1500 mL). Aq 6 N HCl (750 ml,4.5 mol) was added. The reaction was stirred at rt for 2-3 h and thenwas concentrated. The residue was diluted with water (2 L), washed withEtOAc (500 ml). The aqueous layer was basified with sat NaHCO₃,extracted into EtOAc (3×1 L). The combined organic layers were washedwith water (1 L) and brine (1 L), dried over Na₂SO₄, filtered andconcentrated under vacuum at 50-55° C. to give crude product (43 g,90%). MS(ESI) m/z: 183.2 (M+H)⁺. The crude product (42 g, 230 mmol) wasdissolved in DCM (420 mL), and Et₃N (32.1 mL, 230 mmol) was addedfollowed by dropwise addition of BOC₂O (53.4 mL, 230 mmol). The reactionwas stirred at rt for 2-3 h. The reaction was diluted with excess DCM (1L), washed with water (500 ml) and brine (500 ml). The organic layer wasdried over Na₂SO₄, filtered, and concentrated. The crude product wasthen purified using silica gel chromatography to give (S)-tert-butyl1-(4-chloropyridin-2-yl)but-3-enylcarbamate (61 g, 86%) as a pale yellowsolid. MS(ESI) m/z: 283.2 (M+H)⁺.

1D. Preparation of 1-methyl-4-nitro-1H-pyrazole

To a solution of 4-nitro-1H-pyrazole (2.5 g, 22.11 mmol) in THF (50 mL)was added NaH (0.973 g, 24.32 mmol) and the mixture was stirred at rtfor 5 min. To this suspension was then added MeI (1.382 mL, 22.11 mmol)and stirred at rt overnight. The reaction mixture was then diluted withEtOAc and washed with brine. The organic layer was concentrated,followed by purification using normal phase chromatography to yield1-methyl-4-nitro-1H-pyrazole a as white solid (1.9 g, 80%). ¹H NMR (400MHz, CDCl₃) δ ppm 8.12 (s, 1H), 8.06 (s, 1H), 3.97 (s, 3H).

1E. Preparation of (S)-tert-butyl(1-(4-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate

To a pressure vial was added (S)-tert-butyl1-(4-chloropyridin-2-yl)but-3-enylcarbamate (3.0 g, 10.61 mmol),1-methyl-4-nitro-1H-pyrazole, (1.348 g, 10.61 mmol),di(adamant-1-yl)(butyl)phosphine (1.141 g, 3.18 mmol), pivalic acid(0.369 ml, 3.18 mmol) and K₂CO₃ (4.40 g, 31.8 mmol). To the reactionmixture was then added DMF (21 mL) and the vial was purged with Ar (3×).To this mixture was then added Pd(OAc)₂ (0.476 g, 2.122 mmol). The vialwas sealed and heated in oil bath at 120° C. overnight. The reactionmixture was filtered and partitioned between aq 10% LiCl (15 mL) andEtOAc (30 mL). The aqueous layer was extracted with EtOAc (2×20 mL) andthe combined organic layers were washed with brine (15 mL) and driedover MgSO₄, filtered and concentrated. The crude product was thenpurified using normal phase chromatography to yield 1.2 g of(S)-tert-butyl(1-(4-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(29%) as a brown oil. MS(ESI) m/z: 374.4 (M+H)⁺.

1F. Preparation of (S)-tert-butyl(1-(4-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate

A solution of (S)-tert-butyl(1-(4-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(1.2 g, 3.21 mmol) in MeOH (10 mL) and AcOH (1 mL) was heated in oilbath to 60° C. To the above clear solution was then slowly added Zn(0.420 g, 6.43 mmol) and allowed to stir at the same temperature for 15min. The reaction mixture was then filtered through CELITE® andconcentrated to yield the crude product. The crude product was thenpurified using normal phase chromatography to yield 0.88 g of(S)-tert-butyl(1-(4-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(76%) as pale brown oil. MS(ESI) m/z: 344.4 (M+H)⁺.

1G. Preparation of tert-butyl((S)-1-(4-(1-methyl-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate

To a solution of (R)-2-methylbut-3-enoic acid, Intermediate 6, (385 mg,3.84 mmol), (S)-tert-butyl(1-(4-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(880 mg, 2.56 mmol) and pyridine (0.620 mL, 7.69 mmol) in EtOAc (40 mL)at −10° C. under Ar was added T3P® (50% wt in EtOAc) (3.05 mL, 5.12mmol) dropwise. The reaction mixture was stirred at −10° C. which wasallowed to gradually warm up to rt. The reaction mixture was thenallowed to stir at rt for 2h. The reaction mixture was then diluted withEtOAc followed by washing with aq sat NaHCO₃ and brine. The organiclayers were pooled together, dried over MgSO₄, filtered andconcentrated. The crude product was then purified using normal phasechromatography to yield 0.6 g of tert-butyl((S)-1-(4-(1-methyl-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(52%) as yellow oil. MS(ESI) m/z: 426.5 (M+H)⁺.

1H. Preparation of tert-butylN-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate

A solution of tert-butyl((S)-1-(4-(1-methyl-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(600 mg, 1.410 mmol) in DCE (18 mL) was purged by bubbling Ar into thereaction mixture. Second Generation Grubbs Catalyst (480 mg, 0.564 mmol)was then added. The reaction mixture was purged with Ar and evacuatedagain (3×). The reaction mixture was then heated at 120° C. in amicrowave vial for 30 min. The reaction mixture was then concentratedand the crude residue was purified using normal phase chromatography toyield 118 mg of tert-butylN-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(20%) as brown oil. MS(ESI) m/z: 398.5 (M+H)⁺.

1I. Preparation of tert-butylN-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate

To a degassed solution of tert-butylN-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(118 mg, 0.297 mmol) in EtOH (12 mL) was added Pd on carbon (31.6 mg,0.030 mmol) and the reaction mixture was then stirred under H₂ at 55 psifor 5 h. The reaction mixture was then filtered though CELITE® andconcentrated to yield tert-butylN-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(92 mg, 72%) as brown oil. MS(ESI) m/z: 400.4 (M+H)⁺.

1J. Preparation of(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

To a solution of tert-butylN-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(92 mg, 0.230 mmol) in MeOH (3 mL) was added 4 M HCl in dioxane (3 mL,12.00 mmol) and the reaction was stirred at rt for 1.5 h. The reactionmixture was then concentrated in vacuo to yield 86 mg of(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-oneas yellow solid. MS(ESI) m/z: 300.4 (M+H)⁺.

1K. Preparation of(9R,13S)-13-({3-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-3-oxopropyl}amino)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

To a solution of(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(34 mg, 0.091 mmol) and1-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one (21.34 mg,0.091 mmol) in DCM (2 mL) was added DIEA (16 μL, 0.092 mmol). Thereaction was then stirred at rt for 15 min. At the end of 15 min, thecrude reaction mixture was used in the next step. MS(ESI) m/z: 533.4(M+H)⁺.

1L. Preparation of[({3-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-3-oxopropyl}[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamoyl)methyl]phosphonate

To the crude reaction mixture,(9R,13S)-13-({3-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-3-oxopropyl}amino)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(49 mg, 0.092 mmol) at 0° C. was added diethyl(2-chloro-2-oxoethyl)phosphonate (276 μl, 0.276 mmol) and the reactionmixture was gradually warmed to rt and was stirred at rt for 30 min. Thereaction mixture was then quenched using 0.2 mL H₂O followed bypurification using reverse phase HPLC. The desired fractions are thenconcentrated using a BIOTAGE® V10 to give 43 mg of[({3-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-3-oxopropyl}[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamoyl)methyl]phosphonateas clear oil. MS(ESI) m/z: 711.4 (M+H)⁺.

1M. Preparation of(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

To a solution of[({3-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-3-oxopropyl}[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamoyl)methyl]phosphonate(43 mg, 0.060 mmol) in MeOH (1.5 mL) at 0° C. was added NaOMe (52.3 mg,0.242 mmol). The ice bath was removed and stirring was continued at rtfor 10 min. The reaction mixture was then quenched with 1 N HCl (0.05mL) and concentrated to give the crude product. The crude product wasthen purified using reverse phase HPLC to afford 21 mg of(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl)}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate as a pale yellow solid. ¹H NMR (400 MHz, CD₃OD-d₄) δ8.76 (d, J=6.4 Hz, 1H), 8.27 (d, J=0.9 Hz, 1H), 7.85 (d, J=1.1 Hz, 1H),7.81-7.77 (m, 2H), 7.62-7.48 (m, 4H), 5.77 (s, 1H), 5.39 (dd, J=12.5,3.7 Hz, 1H), 4.05 (s, 3H), 3.42 (t, J=6.9 Hz, 2H), 2.57-2.45 (m, 1H),2.23-2.06 (m, 3H), 1.95-1.82 (m, 2H), 1.61-1.48 (m, 1H), 1.34-1.24 (m,1H), 1.13 (d, J=6.8 Hz, 2H), 1.07-1.02 (m, 3H). MS(ESI) m/z: 557.4(M+H). Analytical HPLC (Method A): RT=5.82 min, purity=>95%; Factor XIaKi=1.8 nM, Plasma Kallikrein Ki=24 nM.

Example 2 Preparation of(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,2,3,6-tetrahydropyridin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-[4-(3-Chloro-2,6-difluorophenyl)-6-oxo-1,2,3,6-tetrahydropyridin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onewas prepared according to the procedures described in Example 1 bysubstituting,1-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one with1-(3-chloro-2,6-difluorophenyl)prop-2-en-1-one, Intermediate 1. ¹H NMR(400 MHz, CD₃OD) δ 8.80 (d, J=5.5 Hz, 1H), 7.84-7.73 (m, 2H), 7.59-7.48(m, 2H), 7.10 (td, J=9.2, 2.0 Hz, 1H), 6.12 (s, 1H), 5.56 (dd, J=12.5,3.7 Hz, 1H), 4.09 (s, 3H), 3.70 (t, J=6.8 Hz, 2H), 2.79-2.68 (m, 2H),2.65-2.53 (m, 1H), 2.33-2.19 (m, 1H), 2.07-1.90 (m, 2H), 1.69-1.56 (m,1H), 1.21 (br. s., 2H), 1.10 (d, J=6.8 Hz, 3H). MS(ESI) m/z: 526.4(M+H). Analytical HPLC (Method A): RT=6.97 min, purity=>95%; Factor XIaKi=10 nM, Plasma Kallikrein Ki=30 nM.

Example 3 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onewas prepared according to the procedures described in Example 1 bysubstituting1-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one, with1-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one,Intermediate 4. ¹H NMR (400 MHz, CD₃OD) δ 8.77 (d, J=5.3 Hz, 1H), 8.48(s, 1H), 7.71-7.57 (m, 4H), 7.54 (s, 1H), 5.86 (s, 1H), 5.55 (dd,J=12.8, 3.7 Hz, 1H), 4.09 (s, 3H), 3.60-3.49 (m, 2H), 2.60 (d, J=5.7 Hz,1H), 2.26 (t, J=6.8 Hz, 2H), 2.18 (d, J=11.2 Hz, 1H), 2.04-1.84 (m, 2H),1.68-1.52 (m, 1H), 1.45-1.31 (m, 2H), 1.20 (d, J=6.6 Hz, 2H), 1.13-1.08(m, 3H). MS(ESI) m/z: 591.3 (M+H). Analytical HPLC (Method A): RT=6.69min, purity=>95%; Factor XIa Ki=0.12 nM, Plasma Kallikrein Ki=6 nM.

Example 4 Preparation of4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-2-oxo-1,2-dihydropyridin-4-yl}benzonitrile

4A. Preparation of(9R,13S)-3-(difluoromethyl)-13-(4-hydroxy-2-oxo-1,2-dihydropyridin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

To a solution of(9R,13S)-13-amino-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.060 g, 0.178 mmol), Intermediate 19, 4-hydroxy-2H-pyran-2-one, in avial was added nBuOH (0.8 mL) and water (0.2 mL). The vessel was cappedand heated at 110° C. for 15 h then cooled to rt. The reaction mixturewas concentrated and purified by normal phase chromatography to give(9R,13S)-3-(difluoromethyl)-13-(4-hydroxy-2-oxo-1,2-dihydropyridin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.0055 g, 7.2%) as a yellow solid. MS(ESI) m/z: 430.0 (M+H).

4B. Preparation of1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-2-oxo-1,2-dihydropyridin-4-yltrifluoromethanesulfonate

To a vial containing(9R,13S)-3-(difluoromethyl)-13-(4-hydroxy-2-oxo-1,2-dihydropyridin-1-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(5.5 mg, 0.013 mmol),1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide(5.49 mg, 0.015 mmol) was added Et₃N (5.36 μl, 0.038 mmol) in DMF (0.3mL). After 1 h at rt, the reaction mixture was concentrated and purifiedby normal phase chromatography to give1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-2-oxo-1,2-dihydropyridin-4-yltrifluoromethanesulfonate (1.8 mg, 25.03% yield) as a yellow solid.MS(ESI) m/z: 562.08 (M+H).

4C. Preparation of4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-2-oxo-1,2-dihydropyridin-4-yl}benzonitriletrifluoroacetate

To a dioxane (0.15 mL) solution of1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-2-oxo-1,2-dihydropyridin-4-yltrifluoromethanesulfonate (1.8 mg, 3.21 μmol),(5-chloro-2-cyanophenyl)boronic acid (0.698 mg, 3.85 μmol) was added aq2 M Na₂CO₃ (3.21 μl, 6.41 μmol). The solution was purged with Ar, andPd(PPh₃)₄ (0.370 mg, 0.321 μmol) was added. The reaction was purged withAr for several min then was capped and heated at 100° C. for 3 h, thencooled to rt. The reaction mixture was concentrated and the residuepurified by reverse phase HPLC to give4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-2-oxo-1,2-dihydropyridin-4-yl}benzonitriletrifluoroacetate (1.62 mg, 2.370 μmol, 73.9% yield) as an white solid.MS(ESI) m/z: 549.4 (M+H). ¹H NMR (500 MHz, CDCl₃) δ 8.74 (d, J=5.0 Hz,1H), 8.36 (d, J=6.9 Hz, 1H), 7.87 (d, J=8.3 Hz, 1H), 7.79-7.72 (m, 1H),7.71 (d, J=1.9 Hz, 1H), 7.68-7.64 (m, 2H), 7.52 (d, J=4.1 Hz, 1H), 6.73(d, J=1.9 Hz, 1H), 6.64 (dd, J=7.3, 2.1 Hz, 1H), 6.19 (dd, J=13.1, 4.3Hz, 1H), 2.76-2.67 (m, 1H), 2.38-2.27 (m, 1H), 2.13-1.98 (m, 2H),1.70-1.57 (m, 1H), 1.55-1.41 (m, 1H), 1.38-1.29 (m, 1H), 1.02 (d, J=6.9Hz, 3H), 0.70 (br. s., 1H). Analytical HPLC (Method A): RT=8.66 min,purity=>99%; Factor XIa Ki=3.2 nM, Plasma Kallikrein Ki=19 nM.

Example 5 Preparation of13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3-cyclopropyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

13-{4-[5-Chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3-cyclopropyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onewas prepared according to the procedures described in Example 1 bysubstituting 1-methyl-4-nitro-1H-pyrazole, Example 1D, with1-cyclopropyl-4-nitro-1H-pyrazole, Intermediate 7. ¹H NMR (500 MHz,CD₃OD) δ 8.75 (d, J=5.5 Hz, 1H), 8.33 (d, J=1.1 Hz, 1H), 7.92 (d, J=1.1Hz, 1H), 7.89-7.85 (m, 1H), 7.70-7.63 (m, 3H), 7.59 (dd, J=8.1, 0.7 Hz,1H), 7.49 (s, 1H), 5.84 (t, J=1.2 Hz, 1H), 5.56-5.48 (m, 1H), 3.98-3.88(m, 1H), 3.64-3.55 (m, 1H), 3.55-3.46 (m, 1H), 2.65-2.54 (m, 1H),2.27-2.11 (m, 3H), 2.03-1.94 (m, 1H), 1.93-1.82 (m, 1H), 1.67-1.53 (m,1H), 1.39-1.28 (m, 1H), 1.28-1.18 (m, 1H), 1.16-1.03 (m, 8H). MS(ESI)m/z: 583.5 (M+H)⁺. Analytical HPLC (Method A): RT=6.11 min, purity=98%;Factor XIa Ki=1.4 nM, Plasma Kallikrein Ki=52 nM.

Example 6 Preparation of(9R,13S)-13-{4-[3-chloro-2-fluoro-6-trifluoromethyl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[3-Chloro-2-fluoro-6-trifluoromethyl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onewas prepared according to the procedures described in Example 1 bysubstituting,1-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one with1-(3-chloro-2-fluoro-6-(trifluoromethyl)phenyl)prop-2-en-1-one,Intermediate 2. ¹H NMR (400 MHz, CD₃OD-d₄) δ 8.74 (d, J=5.5 Hz, 1H),7.76 (s, 1H), 7.72 (dd, J=5.6, 1.2 Hz, 1H), 7.67-7.61 (m, 1H), 7.56-7.51(m, 1H), 7.47 (s, 1H), 5.87 (s, 1H), 5.47 (dd, J=12.5, 3.7 Hz, 1H), 4.01(s, 3H), 3.65 (br. s., 2H), 2.55-2.44 (m, 2H), 2.25-2.12 (m, 1H),1.98-1.84 (m, 2H), 1.60-1.48 (m, 1H), 1.13 (br. s., 2H), 1.02 (d, J=6.8Hz, 3H). MS(ESI) m/z: 576.1 (M+H). Analytical HPLC (Method A): RT=8.27min, purity=97%; Factor XIa Ki=1.7 nM, Plasma Kallikrein Ki=7 nM.

Example 7 Preparation of13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3-ethyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

13-{4-[5-Chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3-ethyl-9-methyl-3,4,7,15tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onewas prepared according to the procedures described in Example 1 bysubstituting 1-methyl-4-nitro-1H-pyrazole with1-ethyl-4-nitro-1H-pyrazole, Intermediate 8. ¹H NMR (400 MHz, CD₃OD) δ8.80 (d, J=5.5 Hz, 1H), 8.35 (d, J=1.1 Hz, 1H), 7.92 (d, J=1.1 Hz, 1H),7.79 (s, 1H), 7.73 (dd, J=5.5, 1.5 Hz, 1H), 7.69-7.63 (m, 2H), 7.62-7.55(m, 2H), 5.84 (s, 1H), 5.48 (dd, J=12.5, 3.7 Hz, 1H), 4.42 (q, J=7.0 Hz,2H), 3.51 (dd, J=7.9, 6.2 Hz, 2H), 2.66-2.51 (m, 1H), 2.30-2.10 (m, 3H),2.02-1.83 (m, 2H), 1.68-1.54 (m, 1H), 1.52 (t, J=7.3 Hz, 3H), 1.17 (br.s., 2H), 1.10 (d, J=6.8 Hz, 3H). MS(ESI) m/z: 571.2 (M+H). AnalyticalHPLC (Method A): RT=9.150 min, purity=97%; Factor XIa Ki=1.3 nM, PlasmaKallikrein Ki=41 nM.

Example 8 Preparation of13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3-(2,2-difluoroethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

13-{4-[5-Chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3-(2,2-difluoroethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onewas prepared according to the procedures described in Example 1 bysubstituting 1-methyl-4-nitro-1H-pyrazole with1-(2,2-difluoroethyl)-4-nitro-1H-pyrazole, Intermediate 9. ¹H NMR (400MHz, CD₃OD) δ 8.82 (d, J=5.5 Hz, 1H), 8.33 (d, J=0.9 Hz, 1H), 7.91 (d,J=1.1 Hz, 1H), 7.78 (s, 1H), 7.73 (dd, J=5.5, 1.3 Hz, 1H), 7.68-7.63 (m,3H), 7.61-7.56 (m, 1H), 6.48-6.15 (m, 1H), 5.84 (s, 1H), 5.49 (dd,J=12.5, 4.0 Hz, 1H), 4.85-4.72 (m, 2H), 3.59-3.45 (m, 2H), 2.64-2.52 (m,1H), 2.26-2.12 (m, 3H), 1.99-1.84 (m, 2H), 1.59 (td, J=13.8, 8.3 Hz,1H), 1.43-1.31 (m, 1H), 1.23-1.14 (m, 1H), 1.09 (d, J=7.0 Hz, 3H).MS(ESI) m/z: 607.2 (M+H). Analytical HPLC (Method A): RT=6.521 min,purity=97%; Factor XIa Ki=11 nM, Plasma Kallikrein Ki=90 nM.

Example 9 Preparation of(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,2,3,6-tetrahydropyridin-1-yl]-4-(2-hydroxypyridin-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one

9A. Preparation of(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,2,3,6-tetrahydropyridin-1-yl]-4-(2-methoxypyridin-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one

(9R,13S)-13-[4-(3-Chloro-2,6-difluorophenyl)-6-oxo-1,2,3,6-tetrahydropyridin-1-yl]-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.045 g, 0.088 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine(0.013 g, 0.088 mmol), 4-iodo-2-methoxypyridine (0.041 g, 0.176 mmol),CuI (3.4 mg, 0.018 mmol), Cs₂CO₃ (0.057 g, 0.176 mmol), and DMF (2 mL)were added to a microwave vial. The mixture was then degassed andback-filled with Ar (3×). Upon sealing the microwave cap, the reactionwas then heated to 125° C. for 30 min in microwave. The mixture waspurified by reverse phase chromatography to yield(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,2,3,6-tetrahydropyridin-1-yl]-4-(2-methoxypyridin-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one(5.9 mg, 11%). MS(ESI) m/z: 619.4 (M+H). ¹H NMR (500 MHz, DMSO-d₆) δ8.83 (s, 1H), 8.68 (d, J=4.9 Hz, 1H), 8.29 (d, J=5.8 Hz, 1H), 7.75 (s,1H), 7.68 (d, J=5.8 Hz, 1H), 7.59 (d, J=4.9 Hz, 2H), 7.34 (s, 1H), 7.27(s, 1H), 6.08 (s, 1H), 5.74-5.62 (m, 1H), 3.93 (s, 4H), 2.77-2.61 (m,3H), 2.20-1.98 (m, 2H), 1.83-1.71 (m, 1H), 1.64-1.50 (m, 1H), 1.42-1.27(m, 1H), 0.98 (d, J=6.7 Hz, 3H), 0.85-0.65 (m, 1H). Analytical HPLC(Method C): RT=1.64 min, purity=100%.

9B. Preparation of(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,2,3,6-tetrahydropyridin-1-yl]-4-(2-hydroxypyridin-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one

(9R,13S)-13-[4-(3-Chloro-2,6-difluorophenyl)-6-oxo-1,2,3,6-tetrahydropyridin-1-yl]-4-(2-methoxypyridin-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one(30 mg, 0.048 mmol) was dissolved in THF (2 mL) and conc. HCl (500 μl,6.00 mmol) was added. The solution was heated to 70° C. for 8 h. Thereaction was then cooled to rt and concentrated to dryness in vacuo. Theresidue was purified by reverse phase chromatography to yield(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,2,3,6-tetrahydropyridin-1-yl]-4-(2-hydroxypyridin-4-yl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one(12 mg, 32%). MS(ESI) m/z: 605.4 (M+H). ¹H NMR (500 MHz, CD₃OD) δ8.80-8.71 (m, 1H), 8.63 (s, 1H), 8.09-8.03 (m, 1H), 8.01-7.95 (m, 1H),7.69-7.62 (m, 1H), 7.61-7.52 (m, 1H), 7.17-7.08 (m, 2H), 7.05-6.99 (m,1H), 6.18-6.12 (m, 1H), 5.68-5.60 (m, 1H), 3.79-3.65 (m, 2H), 2.89-2.79(m, 1H), 2.79-2.67 (m, 2H), 2.33-2.21 (m, 1H), 2.19-2.05 (m, 2H),1.83-1.69 (m, 1H), 1.50-1.29 (m, 3H), 1.19 (d, J=6.9 Hz, 3H). AnalyticalHPLC (Method A): RT=6.22 min, purity=96%. Factor XIa Ki=14 nM, PlasmaKallikrein Ki=14 nM.

Example 10 Preparation of(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,2,3,6-tetrahydropyridin-1-yl]-3-ethyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-[4-(3-Chloro-2,6-difluorophenyl)-6-oxo-1,2,3,6-tetrahydropyridin-1-yl]-3-ethyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onewas prepared according to the procedures described in Example 1 bysubstituting 1-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-onewith 1-(3-chloro-2,6-difluorophenyl)prop-2-en-1-one, Intermediate 1, andby substituting 1-methyl-4-nitro-1H-pyrazole with1-ethyl-4-nitro-1H-pyrazole, Intermediate 8. ¹H NMR (400 MHz, CD₃OD) δ8.84 (d, J=5.5 Hz, 1H), 7.86 (s, 1H), 7.76 (dd, J=5.7, 1.5 Hz, 1H), 7.61(s, 1H), 7.56 (td, J=8.7, 5.5 Hz, 1H), 7.12 (td, J=9.2, 1.8 Hz, 1H),6.13 (s, 1H), 5.56 (dd, J=12.5, 4.0 Hz, 1H), 4.43 (q, J=7.1 Hz, 2H),3.74 (t, J=6.8 Hz, 2H), 2.85-2.69 (m, 2H), 2.65-2.54 (m, 1H), 2.38-2.20(m, 1H), 2.10-1.88 (m, 2H), 1.71-1.58 (m, 1H), 1.53 (t, J=7.3 Hz, 3H),1.22 (br. s., 2H), 1.12 (d, J=6.8 Hz, 3H). MS(ESI) m/z: 540.2 (M+H)⁺.Analytical HPLC (Method A): RT=11.04 min, purity=97%. Factor XIa Ki=14nM, Plasma Kallikrein Ki=50 nM.

Example 11 Preparation of13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

11A. Preparation of3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

DMF (0.7 ml) was added to a vial containing4-nitro-1-(2,2,2-trifluoroethyl)-1H-pyrazole,4-nitro-1-(2,2,2-trifluoroethyl)-1H-pyrazole, Intermediate 10, (0.02 g,0.037 mmol), Cs₂CO₃ (0.024 g, 0.074 mmol), and(2-bromoethoxy)(tert-butyl)dimethylsilane (0.026 g, 0.110 mmol). Thesuspension was heated to 75° C. for 25 min then concentrated at rt. Thecrude product was used in the subsequent step.

11B. Preparation of13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

To3-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onewas added MeOH (0.7 ml) and conc. HCl (0.05 ml, 0.60 mmol) and thereaction was stirred for 10 min. The crude product was purified byreverse phase preparative HPLC to yield13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-oneas a white solid (6 mg, 8.22 μmol, 22.2% yield). ¹H NMR (500 MHz, CD₃OD)δ 8.76-8.70 (m, 1H), 8.34-8.30 (m, 1H), 7.93-7.88 (m, 1H), 7.84-7.78 (m,1H), 7.68-7.62 (m, 3H), 7.60 (s, 3H), 5.89-5.81 (m, 1H), 5.59-5.50 (m,1H), 4.44-4.38 (m, 2H), 4.05-3.97 (m, 3H), 3.51-3.45 (m, 2H), 2.61-2.51(m, 1H), 2.23-2.09 (m, 3H), 1.99-1.81 (m, 2H), 1.65-1.53 (m, 1H),1.39-1.28 (m, 2H), 1.19-1.12 (m, 2H), 1.12-1.08 (m, 3H). MS(ESI) m/z:587.5 (M+H)⁺. Analytical HPLC (Method A): RT=5.33 min, purity=96%;Factor XIa Ki=5.5 nM, Plasma Kallikrein Ki=140 nM.

Example 12 Preparation of2-(13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-4-yl)aceticacid

12A. Preparation of2-(13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-4-yl)acetate

2-(13-{4-[5-Chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-4-yl)acetatewas prepared according to the procedures described in Example 11 bysubstituting (2-bromoethoxy)(tert-butyl)dimethylsilane with ethyl2-bromoacetate. ¹H NMR (400 MHz, CD₃OD) δ 8.69-8.62 (m, 1H), 8.37-8.34(m, 1H), 8.31-8.26 (m, 1H), 8.03-7.98 (m, 1H), 7.96-7.91 (m, 1H),7.89-7.84 (m, 1H), 7.70-7.64 (m, 2H), 7.63-7.58 (m, 1H), 5.89-5.82 (m,1H), 5.48-5.38 (m, 1H), 5.17-5.13 (m, 2H), 4.34-4.23 (m, 2H), 2.92-2.83(m, 1H), 2.41-2.28 (m, 1H), 2.25-2.16 (m, 2H), 2.03-1.87 (m, 2H),1.76-1.64 (m, 1H), 1.61-1.49 (m, 1H), 1.32 (s, 4H), 1.26-1.20 (m, 3H).MS(ESI) m/z: 629.4 (M+H)⁺. Analytical HPLC (Method A): RT=5.33 min,purity=96%.

12B. Preparation of2-(13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-4-yl)aceticacid

To a solution of2-(13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-4-yl)acetate(16 mg, 0.025 mmol) in THF (1 mL) was added LiOH (0.216 mL, 0.432 mmol)and the reaction was stirred at rt for 1 h. After 1 h, the reactionmixture was concentrated and the residue purified by reverse phase HPLCpurification to afford 9.5 mg of2-(13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-4-yl)aceticacid (50%) as white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.71 (d, J=6.2 Hz,1H), 8.34 (d, J=1.1 Hz, 1H), 8.15 (s, 1H), 8.09 (dd, J=5.9, 1.5 Hz, 1H),7.92 (d, J=1.1 Hz, 1H), 7.90-7.89 (m, 1H), 7.69-7.56 (m, 3H), 5.82 (s,1H), 5.42 (dd, J=11.2, 3.3 Hz, 1H), 5.11 (d, J=0.9 Hz, 2H), 3.49-3.39(m, 1H), 3.42-3.40 (m, 1H), 2.67-2.54 (m, 1H), 2.34-1.94 (m, 5H),1.79-1.64 (m, 1H), 1.63-1.49 (m, 1H), 1.31 (d, J=7.0 Hz, 1H), 1.19 (d,J=7.0 Hz, 3H). MS(ESI) m/z: 601.4 (M+H). Analytical HPLC (Method A):RT=4.99 min, purity=>95%; Factor XIa Ki=14 nM, Plasma Kallikrein Ki=480nM.

Example 13 Preparation of(9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-10-fluoro-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate, isomer A

13A. Preparation of tert-butylN-[(9S,13S)-10-fluoro-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate

In a 250 ml RBF, Fe₂(C₂O₄)₃.6H₂O (449 mg, 0.928 mmol) in water (20 mL)was stirred in a warm water bath until dissolved into a clear yellowsolution. SELECTFLUOR® (329 mg, 0.928 mmol) was added, followed byadding tert-butylN-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(123 mg, 0.309 mmol), which was prepared as in Example 1, in ACN (20mL), followed by adding NaBH₄ (94 mg, 2.476 mmol) portionwise andstirred at rt for 1 h. The reaction mixture was quenched with 28%-30% aqNH₄OH (10 ml), extracted with 10% MeOH in DCM (200 ml, 3×). The combinedorganic phase was washed with brine, dried over MgSO₄, filtered andconcentrated. Purification by reverse phase chromatography, followed byneutralization gave tert-butylN-[(9S,13S)-10-fluoro-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(35.4 mg, 27%), as a white solid and as a mixture of stereo- andregio-diastereomers. MS(ESI) m/z: 418.1 (M+H).

13B1 and 13B2. Preparation of tert-butylN-[(9S,13S)-10-fluoro-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate,isomer A (13B1), and tert-butylN-[(9S,13S)-10-fluoro-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate,isomer B (13B2)

tert-ButylN-[(9S,13S)-10-fluoro-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(35.4 mg), a mixture of diastereomers, was resolved by chiral SFCseparation. Column: Lux 5. Cellulose-4, 21×250 mm, 5μ. Mobile Phase: 15%MeOH-0.1% DEA/85% CO₂, Flow Conditions: 45 mL/min, 150 Bar, 40° C. 1stpeak fraction gave 20 mg of 13B1 as a white solid which was labeled assingle isomer A; and the 2nd peak fraction was concentrated to give 10mg of 13B2 as a white solid which was labeled as single isomer B.

13C. Preparation of(9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-10-fluoro-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate, isomer A

(9S,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-10-fluoro-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate, isomer A (0.0150 g, 61%) was prepared according to theprocedures described in Example 1, by using1-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one andtert-butylN-[(9S,13S)-10-fluoro-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate.MS(ESI) m/z: 609.1 (M+H). ¹H NMR (400 MHz, CD₃OD) δ 8.72 (d, J=5.3 Hz,1H), 8.44 (s, 1H), 7.63-7.59 (m, 2H), 7.57-7.50 (m, 2H), 7.47-7.44 (m,2H), 5.78 (s, 1H), 5.67 (dd, J=12.7, 5.4 Hz, 1H), 5.27-5.09 (m, 1H),4.22-4.14 (m, 1H), 4.01 (s, 3H), 3.70 (ddd, J=12.5, 9.7, 5.1 Hz, 1H),3.12-3.01 (m, 1H), 2.43-2.32 (m, 1H), 2.31-2.21 (m, 1H), 2.20-2.10 (m,1H), 2.03-1.92 (m, 1H), 1.71-1.55 (m, 1H), 0.93 (d, J=6.8 Hz, 3H),0.62-0.40 (m, 1H). Analytical HPLC (Method A): RT=8.16 min, purity=>99%;Factor XIa Ki=0.1 nM, Plasma Kallikrein Ki=6 nM.

Example 14 Preparation of(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(trifluoromethyl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[3-Chloro-2-fluoro-6-(trifluoromethyl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(25 mg, 53%). was prepared in a similar manner to Example 1 by using1-(difluoromethyl)-4-nitro-1H-pyrazole, Intermediate 14, and-(3-chloro-2-fluoro-6-(trifluoromethyl)phenyl)prop-2-en-1-one,Intermediate 2. MS(ESI) m/z: 612.3 (M+H). ¹H NMR (400 MHz, CD₃CN) δ8.87-8.73 (m, 1H), 7.82-7.36 (m, 7H), 5.93 (s, 1H), 5.66-5.52 (m, 1H),4.23-4.03 (m, 1H), 3.97-3.83 (m, 1H), 3.82-3.66 (m, 1H), 2.73-2.46 (m,3H), 2.34-2.17 (m, 1H), 1.66-1.48 (m, 2H), 1.38-1.18 (m, 3H), 1.01 (d,J=6.8 Hz, 4H), 0.85-0.71 (m, 1H). Analytical HPLC (Method A): RT=9.88min, purity=94%; Factor XIa Ki=1 nM, Plasma Kallikrein Ki=110 nM.

Example 15 Preparation of(9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-10-fluoro-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate, isomer B

(9S,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-10-fluoro-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate, isomer B (0.0081 g, 62%) was prepared according to theprocedures described in Example 13, by replacing tert-butylN-[(9S,13S)-10-fluoro-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamatewith tert-butylN-[(9S,13S)-10-fluoro-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate,isomer B, prepared as intermediate 13B2. MS(ESI) m/z: 609.1 (M+H). ¹HNMR (500 MHz, methanol-d₄) δ 8.80 (d, J=5.5 Hz, 1H), 8.45 (s, 1H), 7.72(dd, J=5.5, 1.4 Hz, 1H), 7.65-7.61 (m, 2H), 7.59-7.57 (m, 2H), 7.56-7.54(m, 2H), 5.84 (d, J=1.4 Hz, 1H), 5.67 (dd, J=12.9, 2.8 Hz, 1H),4.50-4.30 (m, 1H), 4.06 (s, 3H), 3.47-3.36 (m, 1H), 3.20-3.05 (m, 1H),2.82-2.53 (m, 2H), 2.33-1.86 (m, 4H), 1.22 (d, J=6.6 Hz, 3H) AnalyticalHPLC (Method A): RT=7.29 min, purity=>95%; Factor XIa Ki=19 nM, PlasmaKallikrein Ki=450 nM.

Example 16 Preparation of2-[(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-3-yl]aceticacid

A solution of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (0.025 g, 0.040 mmol), prepared as described in Example35, in acetone (2 mL) was cooled to 0° C. To this cooled mixture wasthen added 2.86 molar solution of Jones reagent (0.028 mL, 0.080 mmol)and the resulting reaction mixture was allowed to warm to rt over aperiod of 2 h. The reaction mixture was then quenched with 0.5 mL of IPAand concentrated. The resulting residue was purified by prep HPLCpurification to afford2-[(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-3-yl]aceticacid trifluoroacetate (4.5 mg, 5.70 μmol, 14% yield) as a white solid.¹H NMR (400 MHz, CD₃OD) δ 8.74-8.65 (m, 1H), 8.47-8.44 (m, 1H),7.68-7.47 (m, 6H), 5.82 (s, 1H), 5.54 (dd, J=12.8, 3.7 Hz, 1H),5.20-5.06 (m, 2H), 4.21-4.07 (m, 1H), 3.61-3.43 (m, 2H), 2.62-2.49 (m,2H), 2.30-2.05 (m, 3H), 1.99-1.77 (m, 2H), 1.66-1.50 (m, 1H), 1.43-1.16(m, 3H). MS(ESI) m/z: 635.4 [M+H]⁺. Analytical HPLC (Method A): RT=6.74min, purity=>95.0%; Factor XIa Ki=0.19 nM, Plasma Kallikrein Ki=17 nM.

Example 17 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3-(H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

17A. Preparation of 1-(²H₃)methyl-4-nitro-1H-pyrazole

DIAD (5.59 mL, 28.7 mmol) was added to a solution of 4-nitro-1H-pyrazole(2.5 g, 22.11 mmol), CD₃OD (0.898 mL, 22.11 mmol), and Ph₃P (resinbound) (8.84 g, 26.5 mmol) in THF (40 mL) and stirred overnight. Thereaction was quenched with water, extracted with EtOAc, washed withbrine, dried over Na₂SO₄, filtered, and concentrated. The crude productwas purified by normal phase chromatography eluting with a gradient ofDCM/MeOH to afford 1-(²H₃)methyl-4-nitro-1H-pyrazole (1.92 g, 14.76mmol, 66.7% yield) as a white solid. MS(ESI) m/z: 131.0 (M+H)⁺. ¹H NMR(400 MHz, CDCl₃) δ 8.13 (d, J=0.4 Hz, 1H), 8.05 (s, 1H).

17B. Preparation of tert-butylN-[(1S)-1-{4-[1-(²H₃)methyl-4-nitro-1H-pyrazol-5-yl]pyridin-2-yl}but-3-en-1-yl]carbamate

To a large microwave vial were added (S)-tert-butyl(1-(4-chloropyridin-2-yl)but-3-en-1-yl)carbamate (2.61 g, 9.22 mmol),1-(²H₃)methyl-4-nitro-1H-pyrazole (1.0 g, 7.69 mmol),di(adamantan-1-yl)(butyl)phosphine (0.413 g, 1.15 mmol), K₂CO₃ (3.19 g,23.06 mmol), pivalic acid (0.268 ml, 2.306 mmol) and DMF (15.37 ml). Thereaction was purged with Ar for 10 min, then Pd(OAc)₂ (0.173 g, 0.769mmol) was added, the vial sealed, and stirred at 115° C. overnight. Thereaction was then partitioned between EtOAc and H₂O. The aqueous layerwas extracted with EtOAc (2×). The combined organic layer was washedwith brine, dried over MgSO₄, filtered and concentrated. The residue waspurified by normal phase chromatography eluting with a gradient ofhexanes/EtOAc to give tert-butylN-[(1S)-1-{4-[1-(²H₃)methyl-4-nitro-1H-pyrazol-5-yl]pyridin-2-yl}but-3-en-1-yl]carbamate(1.49 g, 3.96 mmol, 51.5% yield) as a lavender foam. MS(ESI) m/z: 377.0(M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.77 (d, J=4.8 Hz, 1H), 8.21 (s, 1H),7.26 (s, 1H), 7.23 (dd, J=5.1, 1.5 Hz, 1H), 5.78-5.65 (m, 1H), 5.55 (d,J=6.8 Hz, 1H), 5.14-5.03 (m, 2H), 4.89 (d, J=6.8 Hz, 1H), 2.66 (t, J=6.6Hz, 2H), 1.44 (s, 9H).

17C. Preparation of tert-butylN-[(1S)-1-{4-[4-amino-1-(²H₃)methyl-1H-pyrazol-5-yl]pyridin-2-yl}but-3-en-1-yl]carbamate

tert-ButylN-[(1S)-1-{4-[1-(²H₃)methyl-4-nitro-1H-pyrazol-5-yl]pyridin-2-yl}but-3-en-1-yl]carbamate(1.45 g, 3.85 mmol) was dissolved in acetone (15 mL)/water (3 mL),cooled to 0° C., and NH₄Cl (1.030 g, 19.26 mmol) and Zn (2.52 g, 38.5mmol) were added and the reaction was allowed to warm to rt. After 1 h,the reaction was filtered and filtrate partitioned with water (30 mL)and EtOAc (50 ml). The aqueous layer was extracted with EtOAc (2×50 mL).The combined organic layer was washed with brine (20 ml), dried (MgSO₄),filtered, and concentrated. The residue was purified by normal phasechromatography eluting with a DCM/MeOH gradient to afford tert-butylN-[(1S)-1-{4-[4-amino-1-(²H₃)methyl-1H-pyrazol-5-yl]pyridin-2-yl}but-3-en-1-yl]carbamate(0.62 g, 46.5%). MS(ESI) m/z: 347.2 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ8.67 (dd, J=5.1, 0.7 Hz, 1H), 7.26-7.23 (m, 2H), 7.21 (dd, J=5.1, 1.5Hz, 1H), 5.79-5.66 (m, 1H), 5.58 (d, J=7.3 Hz, 1H), 5.11-5.05 (m, 2H),4.86 (q, J=6.6 Hz, 1H), 2.64 (t, J=6.7 Hz, 2H), 1.44 (s, 9H).

17D. Preparation of tert-butylN-[(1S)-1-{4-[1-(²H₃)methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl]pyridin-2-yl}but-3-en-1-yl]carbamate

(R)-2-Methylbut-3-enoic acid (233 mg, 2.327 mmol), tert-butylN-[(1S)-1-{4-[4-amino-1-(²H₃)methyl-1H-pyrazol-5-yl]pyridin-2-yl}but-3-en-1-yl]carbamate(620 mg, 1.79 mmol), pyridine (0.433 ml, 5.37 mmol) in EtOAc (17.900 mL)was cooled to −10° C. under Ar followed by dropwise addition of T3P®(50% wt in EtOAc) (2.131 ml, 3.58 mmol and then the reaction mixture wasgradually warmed up to rt. After 3.5 h, the reaction mixture was dilutedwith EtOAc, washed with 1.5 M K₂HPO₄ followed by brine, dried overNa₂SO₄, filtered, and concentrated. The crude product was then purifiedby normal phase chromatography eluting with a gradient of hexanes/EtOActo give tert-butylN-[(1S)-1-{4-[1-(²H₃)methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl]pyridin-2-yl}but-3-en-1-yl]carbamate.(529 mg, 1.234 mmol, 69.0% yield) as a yellow foam. MS(ESI) m/z: 429.2(M+H)⁺.

17E. Preparation of tert-butylN-[(9R,10E,13S)-3-(²H₃)methyl-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate

Five large microwave vials were charged in equal amounts with thefollowing: tert-butylN-[(1S)-1-{4-[1-(²H₃)methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl]pyridin-2-yl}but-3-en-1-yl]carbamate(0.51 g, 1.190 mmol) in degassed DCE (90 mL) was irradiated 120° C. for30 min in the presence of Second Generation Grubbs Catalyst (0.404 g,0.476 mmol). The reactions were combined, concentrated, and the residuepurified by normal phase column chromatography eluting with a gradientof hexanes/EtOAc to give tert-butylN-[(9R,10E,13S)-3-(²H₃)methyl-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(0.124 g, 26.0%) as a brown solid. MS(ESI) m/z: 401.2 (M+H)⁺. ¹H NMR(400 MHz, CDCl₃) δ 8.66 (d, J=5.1 Hz, 1H), 7.52 (s, 1H), 7.19 (d, J=4.8Hz, 1H), 6.80 (s, 1H), 6.37 (d, J=7.5 Hz, 1H), 5.68 (t, J=11.2 Hz, 1H),4.82-4.63 (m, 2H), 3.12-2.93 (m, 2H), 1.93 (q, J=11.1 Hz, 1H), 1.48 (s,9H), 1.15 (d, J=5.9 Hz, 3H).

17F. Preparation of tert-butylN-[(9R,13S)-3-(²H₃)methyl-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate

PtO₂ (6.80 mg, 0.030 mmol) was added to a stirring solution oftert-butylN-[(9R,10E,13S)-3-(²H₃)methyl-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(0.120 g, 0.300 mmol) in EtOH (10 mL). The suspension was subjected to aH₂ atmosphere (55 psi) for 1 h. The catalyst was filtered off through aplug of CELITE® and the filtrate concentrated. The product (0.104 g,86%) was carried forward to the next reaction as is without furtherpurification. MS(ESI) m/z: 403.2 (M+H)⁺.

17G. Preparation of(9R,13S)-13-amino-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

4 M HCl in dioxane (1.6 ml) was added to a stirring solution oftert-butylN-[(9R,13S)-3-(²H₃)methyl-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(0.100 g, 0.248 mmol) in MeOH (3 mL). After stirring overnight, thereaction mixture was concentrated to dryness and placed under highvacuum. The hydrogen chloride salt was free based by dissolution inMeOH, passing through a resin bound NaHCO₃ cartridge (StratoSpheres SPE;500 mg, 0.90 mmol loading) and the filtrate concentrated. The materialwas carried forward as is to next reaction. MS(ESI) m/z: 303.4 (M+H)⁺.

17H. Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (14 mg, 33% yield) was prepared according to theprocedures described in Example 1 by using(9R,13S)-13-amino-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one and1-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one,Intermediate 4. MS(ESI) m/z: 594.1 (M+H)⁺. ¹H NMR: (500 MHz,methanol-d₄) δ 8.78 (br. s., 1H), 8.48 (s, 1H), 7.73-7.52 (m, 7H), 5.85(s, 1H), 5.60-5.55 (m, 1H), 3.58-3.51 (m, 2H), 2.61-2.56 (m, 1H), 2.25(t, J=6.7 Hz, 2H), 2.20-2.15 (m, 1H), 2.00-1.86 (m, 3H), 1.61 (dd,J=13.3, 5.9 Hz, 1H), 1.23-1.19 (m, 1H), 1.10 (d, J=6.9 Hz, 3H).Analytical HPLC (Method A): RT=5.94 min, purity=92%; Factor XIa Ki=0.15nM, Plasma Kallikrein Ki=10 nM.

Example 18 Preparation of(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(trifluoromethyl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[3-Chloro-2-fluoro-6-(trifluoromethyl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo-[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (17.6 mg, 39%) was prepared similarto procedures described in Example 1 by using(9R,13S)-13-amino-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,prepared as described for Example 17G and1-(3-chloro-2-fluoro-6-(trifluoromethyl)phenyl)prop-2-en-1-one,Intermediate 2. MS(ESI) m/z: 579.1 (M+H)⁺. ¹H NMR: (500 MHz, CD₃OD) δ8.78 (br. s., 1H), 8.48 (s, 1H), 7.73-7.52 (m, 7H), 5.85 (s, 1H),5.60-5.55 (m, 1H), 3.58-3.51 (m, 2H), 2.61-2.56 (m, 1H), 2.25 (t, J=6.7Hz, 2H), 2.20-2.15 (m, 1H), 2.00-1.86 (m, 3H), 1.61 (dd, J=13.3, 5.9 Hz,1H), 1.23-1.19 (m, 1H), 1.10 (d, J=6.9 Hz, 3H). Analytical HPLC (MethodA): RT=7.26 min, purity=95%; Factor XIa Ki=2.8 nM, Plasma KallikreinKi=30 nM.

Example 19 Preparation of4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,2,3,6-tetrahydropyridin-4-yl}benzonitrile

19A. Preparation of(9R,13S)-13-[4-(2-bromo-5-chlorophenyl)-6-oxo-1,2,3,6-tetrahydropyridin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-[4-(2-Bromo-5-chlorophenyl)-6-oxo-1,2,3,6-tetrahydropyridin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(35 mg, 47%) was prepared in a similar manner to Example 1 by using1-(6-bromo-3-chloro-2-fluorophenyl)prop-2-en-1-one and1-(difluoromethyl)-4-nitro-1H-pyrazole. MS(ESI) m/z: 604.2 (M+H) and606.2 (M+2+H).

19B. Preparation of4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,2,3,6-tetrahydropyridin-4-yl}benzonitrile

4-Chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,2,3,6-tetrahydropyridin-4-yl}benzonitrilewas prepared from(9R,13S)-13-[4-(2-bromo-5-chlorophenyl)-6-oxo-1,2,3,6-tetrahydropyridin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onein a similar manner to the procedures described in Example 1 to yield4-chloro-2-{1-[(9R,13S)-3-(difluoromethyl)-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,2,3,6-tetrahydropyridin-4-yl}benzonitrile(9 mg, 26%). MS(ESI) m/z: 551.3 (M+H). ¹H NMR (400 MHz, CD₃CN) δ 8.80(d, J=5.5 Hz, 1H), 7.85-7.71 (m, 4H), 7.71-7.36 (m, 4H), 6.20 (s, 1H),5.53 (dd, J=12.7, 4.3 Hz, 1H), 3.95-3.83 (m, 1H), 3.82-3.72 (m, 1H),2.81 (t, J=6.6 Hz, 2H), 2.56 (td, J=7.2, 3.1 Hz, 1H), 2.28 (dd, J=6.4,3.5 Hz, 1H), 1.95-1.85 (m, 2H), 1.65-1.51 (m, 1H), 1.41-1.21 (m, 2H),1.06-0.98 (m, 3H), 0.96-0.74 (m, 2H). Analytical HPLC (Method A):RT=8.24 min, purity=96%; Factor XIa Ki=1.4 nM, Plasma Kallikrein Ki=10nM.

Example 20 Preparation of(9S,13S)-13-{4-[3-chloro-2-fluoro-6-(trifluoromethyl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-10-fluoro-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9S,13S)-13-{4-[3-Chloro-2-fluoro-6-(trifluoromethyl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-10-fluoro-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (0.0144 g, 66%) was prepared according to theprocedures described in Example 13, by replacing1-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-onewith 1-(3-chloro-2-fluoro-6-(trifluoromethyl)phenyl)prop-2-en-1-one,intermediate 2. MS(ESI) m/z: 594.2 (M+H). ¹H NMR (400 MHz, CD₃OD) δ 8.76(d, J=5.3 Hz, 1H), 7.73-7.66 (m, 1H), 7.60 (d, J=8.6 Hz, 1H), 7.55-7.44(m, 3H), 5.93 (s, 1H), 5.79 (dd, J=12.7, 5.4 Hz, 1H), 5.33-5.14 (m, 1H),4.49-4.38 (m, 1H), 4.03 (s, 3H), 3.97-3.87 (m, 1H), 3.15-3.05 (m, 1H),2.90-2.49 (m, 2H), 2.30-2.19 (m, 1H), 2.13-2.00 (m, 1H), 1.77-1.59 (m,1H), 0.96 (d, J=6.8 Hz, 3H), 0.67-0.45 (m, 1H). Analytical HPLC (MethodA): RT=8.39 min, purity=>98%; Factor XIa Ki=1.4 nM, Plasma KallikreinKi=40 nM.

Example 21 Preparation of(9R,13S)-13-{4-[3-chloro-6-(difluoromethoxy)-2-fluorophenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[3-Chloro-6-(difluoromethoxy)-2-fluorophenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(28 mg, 79%) was prepared in a similar manner to Example 1 by using1-(difluoromethyl)-4-nitro-1H-pyrazole, Intermediate 14, and1-(3-chloro-6-(difluoromethoxy)-2-fluorophenyl)prop-2-en-1-one,Intermediate 16. MS(ESI) m/z: 610.3 (M+H). ¹H NMR (500 MHz, CD₃OD) δ8.85-8.74 (m, 1H), 7.79 (s, 1H), 7.69 (s, 2H), 7.65-7.51 (m, 2H),7.16-7.09 (m, 1H), 6.92 (s, 1H), 6.03 (s, 1H), 5.69-5.60 (m, 1H),3.93-3.81 (m, 1H), 3.80-3.69 (m, 1H), 2.75-2.57 (m, 3H), 2.33-2.16 (m,1H), 2.06-1.87 (m, 2H), 1.72-1.53 (m, 1H), 1.41-1.19 (m, 2H), 1.09 (d,J=6.9 Hz, 3H), 0.95-0.83 (m, 1H). Analytical HPLC (Method A): RT=9.60min, purity=99%; Factor XIa Ki=0.69 nM, Plasma Kallikrein Ki=40 nM.

Example 22 Preparation of(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,2,3,6-tetrahydropyridin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-[4-(3-Chloro-2,6-difluorophenyl)-6-oxo-1,2,3,6-tetrahydropyridin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(22 mg, 54%). was prepared in a similar manner to Example 1 by using1-(difluoromethyl)-4-nitro-1H-pyrazole, Intermediate 14, and1-(3-chloro-2,6-difluorophenyl)prop-2-en-1-one, Intermediate 1. MS(ESI)m/z: 562.3 (M+H). ¹H NMR (400 MHz, CD₃CN) δ 8.78 (d, J=5.3 Hz, 1H), 7.73(s, 1H), 7.65 (s, 1H), 7.53 (s, 2H), 7.15-7.01 (m, 1H), 6.08 (s, 1H),5.67-5.55 (m, 1H), 3.93-3.80 (m, 1H), 3.80-3.66 (m, 1H), 2.67 (s, 2H),2.62-2.47 (m, 2H), 2.30-2.17 (m, 1H), 1.66-1.47 (m, 1H), 1.41-1.16 (m,2H), 1.02 (d, J=6.8 Hz, 3H), 0.91-0.69 (m, 1H). Analytical HPLC (MethodA): RT=9.03 min, purity=98%; Factor XIa Ki=8 nM, Plasma Kallikrein Ki=50nM.

Example 23 Preparation of(9R,13S)-13-{4-[3-chloro-6-(difluoromethoxy)-2-fluorophenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[3-Chloro-6-(difluoromethoxy)-2-fluorophenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (21 mg, 0.025 mmol, 31% yield) was prepared accordingto the procedures described in Example 1 by substituting1-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one with1-[3-chloro-6-(difluoromethoxy)-2-fluorophenyl]prop-2-en-1-one,Intermediate 16. ¹H NMR (400 MHz, CD₃OD) δ 8.80 (d, J=5.5 Hz, 1H), 7.83(s, 1H), 7.79 (dd, J=5.6, 1.4 Hz, 1H), 7.57-7.48 (m, 2H), 7.13-7.05 (m,1H), 6.89 (s, 1H), 6.71 (s, 1H), 6.00 (s, 1H), 5.53 (dd, J=12.5, 3.7 Hz,1H), 4.08 (s, 3H), 3.67 (t, J=6.9 Hz, 2H), 2.76-2.50 (m, 3H), 2.34-2.18(m, 1H), 2.08-1.88 (m, 2H), 1.69-1.53 (m, 1H), 1.21 (br. s., 2H), 1.09(d, J=6.8 Hz, 3H). MS(ESI) m/z: 574.3 [M+H]⁺. Analytical HPLC (MethodA): RT=7.63 min, purity=>95.0%; Factor XIa Ki=0.92 nM, Plasma KallikreinKi=7 nM.

Example 24 Preparation of(9R,13S)-13-[4-(3,6-dichloro-2-fluorophenyl)-6-oxo-1,2,3,6-tetrahydropyridin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-[4-(3,6-Dichloro-2-fluorophenyl)-6-oxo-1,2,3,6-tetrahydropyridin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (0.016 g, 61% yield) was prepared in a similar manneras the procedure described in Example 2, by replacing1-(3-chloro-2,6-difluorophenyl)prop-2-en-1-one with1-(3,6-dichloro-2-fluorophenyl)prop-2-en-1-one (0.032 g, 0.039 mmol),prepared as described in Example 31A. MS(ESI) m/z: 542.2 (M+H)⁺. ¹H NMR(400 MHz, CD₃OD) d 8.79 (d, J=5.5 Hz, 1H), 7.77 (s, 1H), 7.71 (dd,J=5.4, 1.7 Hz, 1H), 7.54-7.47 (m, 2H), 7.34 (dd, J=8.7, 1.7 Hz, 1H),5.98 (t, J=1.3 Hz, 1H), 5.58 (dd, J=12.5, 4.0 Hz, 1H), 4.08 (s, 3H),3.74 (t, J=7.0 Hz, 2H), 2.73-2.53 (m, 3H), 2.31-2.19 (m, 1H), 2.04-1.91(m, 2H), 1.67-1.55 (m, 1H), 1.28-1.14 (m, 2H), 1.09 (d, J=6.8 Hz, 3H).Analytical HPLC (Method A): RT=7.36 min, 99.5% purity; Factor XIa Ki=2.7nM, Plasma Kallikrein Ki=6 nM.

Example 25 Preparation of(9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

25A. Preparation of 2-isopropylbut-3-enoic acid

To a flame-dry RBF was added 2 M DIA in THF (3.64 ml, 25.6 mmol) and THF(58.1 ml). The reaction was cooled to −78° C. and 1.6 M nBuLi in hexanes(15.97 ml, 25.6 mmol) was added. The reaction was stirred at −78° C. for30 min and but-3-enoic acid (0.990 ml, 11.62 mmol) was added and thereaction was stirred for additional 30 min. Then at −78° C. iPrI (1.739ml, 17.42 mmol) was added and the reaction was slowly warmed to rt over2 h and then stirred at rt overnight. The reaction was quenched with sataq NH₄Cl (15 ml) and then the pH of the solution was adjusted to <4using 1 N HCl. The reaction was extracted with EtOAc (3×30 mL). Thecombined EtOAc layer was washed with brine (40 mL) and dried over MgSO₄,filtered and concentrated. The residue was purified using ISCO system(0-50% EtOAc/Hex gradient) to give 2-isopropylbut-3-enoic acid (800 mg,6.24 mmol, 53.7% yield) as a clear liquid. ¹H NMR (400 MHz, CDCl₃) δ5.98-5.65 (m, 1H), 5.33-5.05 (m, 2H), 2.73 (t, J=8.8 Hz, 1H), 2.08-1.95(m, 1H), 1.09-0.74 (m, 6H).

25B. Preparation of tert-butyl((1S-[1-(4-{1-methyl-4-[2-(propan-2-yl)but-3-enamido]-1H-pyrazol-5-yl}pyridin-2-yl)but-3-en-1-yl]carbamate

To a RBF was added (S)-tert-butyl(1-(4-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate,prepared as described in Example 1F, (765 mg, 2.228 mmol), EtOAc (20mL), 2-isopropylbut-3-enoic acid (286 mg, 2.228 mmol), and pyridine(0.540 mL, 6.68 mmol). The solution was cooled in a brine/ice bath and50% T3P® (1.989 mL, 3.34 mmol) was added. The reaction was stirred at 0°C. for 10 min and then at rt for 60 min. The reaction was diluted withEtOAc (30 mL) and washed with sat NaHCO₃ (20 mL), water (30 mL) andbrine (30 mL). The organic layer was separated, dried over MgSO₄,filtered and concentrated. The residue was purified using ISCO system(0-100% EtOAc/Hex gradient) to give tert-butyl((1S)-1-(4-(4-(2-isopropylbut-3-enamido)-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(850 mg, 1.874 mmol, 84% yield) as diastereomer mixture as a yellowsolid. MS(ESI) m/z: 454.2 (M+H)⁺.

25C1 and 25C2. Preparation of tert-butylN-[(9S,10E,13S)-3-methyl-8-oxo-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate,and tert-Butyl N-[(9R,10E,13S)-3-methyl-8-oxo-9-(propan-2-yl)-3,4,7,15tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate

To a microwave vial was added tert-butyl((1S)-1-(4-(4-(2-isopropylbut-3-enamido)-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(250 mg, 0.551 mmol) and DCE (15 mL). The reaction was purged with Arfor 1 min, then Second Generation Grubbs Catalyst (187 mg, 0.220 mmol)was added. The reaction was sealed and heated at microwave at 120° C.for 60 min. The reaction was then concentrated and the residue waspurified using reverse phase preparative HPLC to give tert-butylN-[(9S,10E,13S)-3-methyl-8-oxo-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamatetrifluoroacetate, 25C1, (50 mg, 0.093 mmol, 16.8% yield), (ESI) m/z:426.2 (M+H)⁺, which has shorter retention time and tert-butylN-[(9R,10E,13S)-3-methyl-8-oxo-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamatetrifluoroacetate 25C2, (50 mg, 0.093 mmol, 16.8% yield), MS(ESI) m/z:426.2 (M+H)⁺ which has longer retention time.

25D. Preparation of tert-butylN-[(9S,13S)-3-methyl-8-oxo-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate

To a 3-neck RBF was added tert-butylN-[(9R,10E,13S)-3-methyl-8-oxo-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamatetrifluoroacetate (25C2) (15 mg, 0.028 mmol), EtOH (3 mL) and PtO₂ (3.16mg, 0.014 mmol). The reaction was stirred under a H₂ atmosphere (balloonpressure) for 1 h. The reaction was filtered through CELITE® and thefiltrate was concentrated to give tert-butylN-[(9S,13S)-3-methyl-8-oxo-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(10 mg, 0.023 mmol, 84% yield) as a brown solid. MS(ESI) m/z: 618.2(M+H)+.

25E. Preparation of(9S,13S)-13-amino-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

To a RBF was added tert-butylN-[(9S,13S)-3-methyl-8-oxo-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(20 mg, 0.047 mmol), dioxane (3 mL), 4 N HCl in dioxane (0.142 mL, 4.68mmol) and MeOH (0.5 mL). The reaction was stirred at rt for 5 min. Thereaction was concentrated and the residue was purified using reversephase preparative HPLC to give(9S,13S)-13-amino-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onehydrochloride. The product was added to a pre-rinsed AgilentStratoSpheres SPE PL-HCO₃ MP Resin cartridge. Gravity filtration,eluting with MeOH, gave a clear, slightly brown filtrate. Concentrationprovided(9S,13S)-13-amino-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(1.5 mg, 3.43 μmol, 7.34% yield) as a beige solid. MS(ESI) m/z: 328.2(M+H)⁺.

25F. Preparation of(9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9S,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onewas prepared according to the procedures described in Example 1 by using1-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one,Intermediate 4, and(9R,13S)-13-amino-3-methyl-9-(propan-2-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one.¹H NMR (400 MHz, CD₃OD) δ 8.79 (d, J=5.3 Hz, 1H), 8.47 (s, 1H), 7.78 (s,1H), 7.74 (dd, J=5.4, 1.2 Hz, 1H), 7.68-7.57 (m, 3H), 7.53 (s, 1H), 5.85(s, 1H), 5.50 (dd, J=12.5, 3.5 Hz, 1H), 4.10 (s, 3H), 3.55-3.40 (m, 2H),2.30-2.13 (m, 3H), 2.10-1.90 (m, 3H), 1.79 (dt, J=9.2, 6.6 Hz, 1H), 1.61(d, J=6.6 Hz, 1H), 1.35 (d, J=3.1 Hz, 1H), 1.19-1.09 (m, 1H), 0.99 (dd,J=6.6, 4.2 Hz, 6H). MS(ESI) m/z: 619.2 (M+H). Analytical HPLC (MethodA): RT=6.67 min, purity=98%; Factor XIa Ki=0.47 nM, Plasma KallikreinKi=16 nM.

Example 26 Preparation of(9R,13S)-13-{4-[3-chloro-6-(difluoromethyl)-2-fluorophenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

26A. Preparation of 3-chloro-6-(difluoromethyl)-2-fluorobenzaldehyde

To a solution of 1-chloro-4-(difluoromethyl)-2-fluorobenzene (373 mg,2.066 mmol) in THF (6 mL) at −78° C. was added LDA inTHF/heptane/ethylbenzene (1.240 mL, 2.479 mmol) dropwise. The solutionturned dark. After continuing to stir at the same temp for 20 min, DMF(0.191 mL, 2.479 mmol) was added and stirred at the same temperature for10 min. AcOH (0.473 mL, 8.26 mmol) was added followed by water (30 mL).The reaction was extracted with EtOAc (30 ml). The EtOAc layer waswashed with water (15 ml) and brine (15 ml), dried over MgSO₄, filteredand concentrated. The residue was purified using ISCO system (0-30%EtOAc/Hex gradient) to give3-chloro-6-(difluoromethyl)-2-fluorobenzaldehyde (400 mg, 1.918 mmol,93% yield) as a light yellow liquid. ¹H NMR (400 MHz, CD₃OD) δ 10.48 (s,1H), 7.80-7.72 (m, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.56-7.27 (t, 1H).

26B. Preparation of1-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)prop-2-en-1-one

1-(3-Chloro-6-(difluoromethyl)-2-fluorophenyl)prop-2-en-1-one wasprepared using a procedure analogous to that used for the preparation ofIntermediate 1 by replacing 3-chloro-2,6-difluorobenzaldehyde with3-chloro-6-(difluoromethyl)-2-fluorobenzaldehyde. ¹H NMR (400 MHz,CDCl₃) δ 7.64-7.55 (m, 1H), 7.47 (d, J=8.4 Hz, 1H), 6.95-6.57 (m, 2H),6.24-6.05 (m, 2H).

26C. Preparation of(9R,13S)-13-{4-[3-chloro-6-(difluoromethyl)-2-fluorophenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[3-Chloro-6-(difluoromethyl)-2-fluorophenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onewas prepared according to the procedures described in Example 1 bysubstituting,1-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one with1-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)prop-2-en-1-one. ¹H NMR(400 MHz, CD₃OD-d₄) δ 8.81 (d, J=5.3 Hz, 1H), 7.77 (s, 1H), 7.72 (dd,J=5.3, 1.5 Hz, 1H), 7.68 (t, J=7.8 Hz, 1H), 7.57-7.49 (m, 2H), 7.03-6.70(m, 1H), 5.99 (s, 1H), 5.61 (dd, J=12.7, 3.9 Hz, 1H), 4.10 (s, 3H), 3.75(t, J=6.8 Hz, 2H), 2.72-2.54 (m, 3H), 2.32-2.19 (m, 1H), 2.08-1.92 (m,2H), 1.64 (dd, J=14.5, 8.8 Hz, 1H), 1.23 (br. s., 2H), 1.12 (d, J=6.8Hz, 3H). MS(ESI) m/z: 558.1 (M+H). Analytical HPLC (Method A): RT=7.13min, purity=98%; Factor XIa Ki=0.48 nM, Plasma Kallikrein Ki=5 nM.

Example 27 Preparation of(9R,13S)-13-{4-[3-chloro-6-(difluoromethoxy)-2-fluorophenyl]-2-oxo-1,2-dihydropyridin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

To a sealed tube containing(9R,13S)-13-{4-[3-chloro-6-(difluoromethoxy)-2-fluorophenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,prepared as described in Example 23, (21 mg, 0.037 mmol), CuI (6.97 mg,0.037 mmol) in DMSO (1 mL) was added 3-iodopyridine (15.00 mg, 0.073mmol) and Cs₂CO₃ (47.7 mg, 0.146 mmol). The reaction mixture was purgedwith Ar (3×), then stirred at 95° C. overnight. The reaction mixture wasconcentrated and purified using prep-HPLC to give(9R,13S)-13-{4-[3-chloro-6-(difluoromethoxy)-2-fluorophenyl]-2-oxo-1,2-dihydropyridin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (1.4 mg, 1.898 μmol, 5.19% yield) as a clear film. ¹HNMR (400 MHz, CD₃OD) δ 8.75 (d, J=5.1 Hz, 1H), 7.76 (s, 1H), 7.67-7.59(m, 1H), 7.56-7.52 (m, 2H), 7.50 (dd, J=8.4, 2.2 Hz, 1H), 7.19 (d, J=9.0Hz, 1H), 7.09-6.68 (m, 1H), 6.61 (s, 1H), 6.48 (d, J=7.7 Hz, 1H), 6.18(dd, J=12.9, 4.3 Hz, 1H), 4.08 (s, 3H), 2.79-2.66 (m, 1H), 2.39-2.28 (m,1H), 2.18-2.01 (m, 2H), 1.71-1.60 (m, 1H), 1.47 (br. s., 1H), 1.06 (d,J=6.8 Hz, 3H), 0.83 (br. s., 1H). MS(ESI) m/z: 572.2 (M+H)⁺. AnalyticalHPLC (Method A): RT=11.21 min, purity=93%; Factor XIa Ki=4.9 nM, PlasmaKallikrein Ki=40 nM.

Example 28 Preparation of(9S,13S)-13-{4-[3-chloro-2-fluoro-6-(trifluoromethyl)phenyl]-2-oxo-1,2-dihydropyridin-1-yl}-10-fluoro-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate

A reaction vial containing(9S,13S)-13-{4-[3-chloro-2-fluoro-6-(trifluoromethyl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-10-fluoro-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate, prepared as described in Example 20, (0.010 g, 0.014mmol), 3-iodopyridine (0.020 g, 0.098 mmol), CuI (0.008 g, 0.042 mmol),Cs₂CO₃ (0.023 g, 0.071 mmol) in DMSO (2 mL) was capped and heated at100° C. for 16 h. After this time, the reaction was cooled to rt. Thereaction mixture was filtered, and concentrated. Purification by reversephase chromatography afforded(9S,13S)-13-{4-[3-chloro-2-fluoro-6-(trifluoromethyl)phenyl]-2-oxo-1,2-dihydropyridin-1-yl}-10-fluoro-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (0.0012 g, 11%) as a beige solid. MS(ESI) m/z: 592.4(M+H). ¹H NMR (400 MHz, CD₃OD) δ 8.81 (d, J=5.1 Hz, 1H), 8.66 (br. s.,1H), 7.85-7.77 (m, 1H), 7.70 (d, J=8.8 Hz, 1H), 7.59 (s, 1H), 7.53 (s,1H), 7.50 (dd, J=5.1, 1.5 Hz, 1H), 6.56 (s, 1H), 6.51 (d, J=7.3 Hz, 1H),5.49-5.29 (m, 1H), 4.07 (s, 3H), 3.25-3.13 (m, 1H), 2.44-2.19 (m, 2H),1.91-1.70 (m, 1H), 1.43-1.28 (m, 1H), 1.02 (d, J=7.0 Hz, 3H), 0.76-0.52(m, 1H). Analytical HPLC (Method A): RT=8.26 min, purity=>92%; FactorXIa Ki=3 nM, Plasma Kallikrein Ki=25 nM.

Example 29 Preparation of(9R,13S)-13-{4-[3-chloro-6-(difluoromethyl)-2-fluorophenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[3-Chloro-6-(difluoromethyl)-2-fluorophenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (18 mg, 43%) was prepared similar to proceduresdescribed in Example 1 by using(9R,13S)-13-amino-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,prepared as described in Example 17G and1-(3-chloro-6-(difluoromethyl)-2-fluorophenyl)prop-2-en-1-one, preparedas described for Example 26. MS(ESI) m/z: 561.2 (M+H)+. ¹H NMR (400 MHz,CD₃OD) δ 8.82 (br. s., 1H), 7.76 (br. s., 1H), 7.71-7.66 (m, 2H),7.56-7.52 (m, 2H), 7.04-6.82 (m, 1H), 6.00 (s, 1H), 5.63 (d, J=10.3 Hz,1H), 3.76 (t, J=6.9 Hz, 2H), 2.69-2.59 (m, 3H), 2.29-2.22 (m, 1H),2.03-1.97 (m, 2H), 1.69-1.61 (m, 1H), 1.24 (d, J=4.2 Hz, 1H), 1.12 (d,J=6.8 Hz, 3H). Analytical HPLC (Method A): RT=6.93 min, purity=95%;Factor XIa Ki=0.6 nM, Plasma Kallikrein Ki=6 nM.

Example 30 Preparation of(9R,13S)-13-{4-[3-chloro-6-(difluoromethoxy)-2-fluorophenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[3-Chloro-6-(difluoromethoxy)-2-fluorophenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (2.1 mg, 18%) was prepared similarto procedures described in Example 1 by using(9R,13S)-13-amino-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,prepared as described for Example 17G and1-(3-chloro-6-(difluoromethoxy)-2-fluorophenyl)prop-2-en-1-one,Intermediate 16. MS(ESI) m/z: 577.3 (M+H)⁺. ¹H NMR (500 MHz, CD₃OD) d7.61-7.54 (m, 2H), 7.15 (d, J=9.1 Hz, 1H), 7.10-6.78 (m, 2H), 6.06 (s,1H), 5.71 (br. s., 1H), 3.85-3.73 (m, 2H), 2.71-2.60 (m, 3H), 2.27-2.21(m, 1H), 2.04-1.95 (m, 2H), 1.65 (td, J=13.5, 8.3 Hz, 1H), 1.28 (d,J=9.9 Hz, 1H), 1.22-1.15 (m, 1H), 1.16-1.07 (m, 3H). Analytical HPLC(Method A): RT=9.98 min, purity=95%; Factor XIa Ki=1 nM, PlasmaKallikrein Ki=7 nM.

Example 31 Preparation of(9R,13S)-13-[4-(3,6-dichloro-2-fluorophenyl)-6-oxo-1,2,3,6-tetrahydropyridin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

31A. Preparation of 1-(3,6-dichloro-2-fluorophenyl)prop-2-en-1-one

1-(3,6-Dichloro-2-fluorophenyl)prop-2-en-1-one was prepared in a similarmanner as the procedure described for the preparation of1-(3-chloro-2,6-difluorophenyl) prop-2-en-1-one, Intermediate 1, byreplacing 3-chloro-2,6-difluorobenzaldehyde, with3,6-dichloro-2-fluorobenzaldehyde. MS(ESI) m/z: 219.0 (M+H)⁺. ¹H NMR(400 MHz, CDCl₃) δ 7.42 (t, J=8.1 Hz, 1H), 7.20 (dd, J=8.7, 1.4 Hz, 1H),6.63 (dd, J=17.6, 10.6 Hz, 1H), 6.23 (d, J=10.3 Hz, 1H), 6.06 (d, J=17.6Hz, 1H).

31B. Preparation of(9R,13S)-13-[4-(3,6-dichloro-2-fluorophenyl)-6-oxo-1,2,3,6-tetrahydropyridin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-[4-(3,6-Dichloro-2-fluorophenyl)-6-oxo-1,2,3,6-tetrahydropyridin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.014 g, 81% yield) was prepared in a similar manner as the proceduredescribed in Example 22, by replacing 1-(3-chloro-2,6-difluorophenyl)prop-2-en-1-one with 1-(3,6-dichloro-2-fluorophenyl)prop-2-en-1-one(8.94 mg, 0.041 mmol). MS(ESI) m/z: 578.1 (M+H)⁺. ¹H NMR (400 MHz,CD₃OD) δ 8.79 (d, J=5.1 Hz, 1H), 7.83-7.67 (m, 3H), 7.61 (d, J=4.8 Hz,1H), 7.55-7.46 (m, 1H), 7.34 (dd, J=8.7, 1.7 Hz, 1H), 5.97 (s, 1H), 5.62(dd, J=12.7, 3.9 Hz, 1H), 3.93-3.73 (m, 2H), 2.73-2.54 (m, 3H),2.30-2.18 (m, 1H), 2.01-1.87 (m, 2H), 1.66-1.54 (m, 1H), 1.30-1.18 (m,1H), 1.10-0.94 (m, 4H). Analytical HPLC (Method A): RT=8.75 min, 100%purity; Factor XIa Ki=1.9 nM, Plasma Kallikrein Ki=11 nM.

Example 32 Preparation of4-chloro-2-{1-[(9R,13S)-3-(²H₃)methyl-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,2,3,6-tetrahydropyridin-4-yl}benzonitrile

4-Chloro-2-{1-[(9R,13S)-3-(²H₃)methyl-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,2,3,6-tetrahydropyridin-4-yl}benzonitriletrifluoroacetate (2.1 mg, 18%) was prepared similar to proceduresdescribed in Example 1 by using(9R,13S)-13-amino-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,prepared as described in Example 17G, and2-acryloyl-4-chlorobenzonitrile, prepared as describe in Example 19.MS(ESI) m/z: 518 (M+H)⁺. ¹H NMR: (400 MHz, CD₃OD) δ 8.80 (br. s., 1H),7.84 (d, J=8.4 Hz, 1H), 7.76 (s, 1H), 7.71-7.66 (m, 2H), 7.62 (dd,J=8.3, 2.1 Hz, 1H), 7.56 (s, 1H), 6.25 (s, 1H), 5.63 (dd, J=12.4, 3.2Hz, 1H), 3.84-3.74 (m, 2H), 2.89-2.82 (m, 2H), 2.65-2.57 (m, 1H),2.32-2.21 (m, 1H), 2.06-1.96 (m, 2H), 1.69-1.60 (m, 1H), 1.12 (d, J=6.8Hz, 3H). Analytical HPLC (Method A): RT=6.22 min, purity=98%; Factor XIaKi=2.4 nM, Plasma Kallikrein Ki=4 nM.

Example 33 Preparation of(9R,13S)-13-{4-[3-chloro-6-(1,1-difluoroethyl)-2-fluorophenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

33A. Preparation of 1-chloro-4-(1,1-difluoroethyl)-2-fluorobenzene

To a tube was added 1-(4-chloro-3-fluorophenyl)ethanone (1 g, 5.79mmol), CH₂Cl₂ (10 mL) and DAST (2.297 mL, 17.38 mmol). The reaction wasthen sealed and stirred at 45° C. for 8 h. The reaction was carefullyquenched with cold sat aq NaHCO₃ over 30 min until the pH was >7. Theorganic layer was separated, washed with water (10 ml), dried overMgSO₄, filtered and concentrated. The residue was purified using ISCOsystem (0-10% EtOAC/Hex gradient) to give1-chloro-4-(1,1-difluoroethyl)-2-fluorobenzene (30 mg, 0.154 mmol, 2.66%yield) as light brown liquid. ¹H NMR (400 MHz, CDCl₃) δ 7.49-7.42 (m,1H), 7.32-7.27 (m, 1H), 7.25-7.20 (m, 1H), 1.90 (t, J=18.2 Hz, 3H).

33B. Preparation of 3-chloro-6-(1,1-difluoroethyl)-2-fluorobenzaldehyde

To a solution of 1-chloro-4-(1,1-difluoroethyl)-2-fluorobenzene (110 mg,0.565 mmol) in THF (2 mL) at −78° C. was added LDA inTHF/heptane/ethylbenzene (0.339 mL, 0.678 mmol) dropwise. The solutionturned dark. After continuing to stir at the same temp for 20 min, DMF(0.052 mL, 0.678 mmol) was added and then the reaction was stirred atthe same temperature for 10 min. AcOH (0.129 mL, 2.261 mmol) was addedfollowed by water (30 mL). The reaction was extracted with EtOAc (30ml). The EtOAc layer was washed with water (15 ml) and brine (15 ml),dried over MgSO₄, filtered and concentrated. The residue was purifiedusing ISCO system (0-30% EtOAc/Hex) to give3-chloro-6-(1,1-difluoroethyl)-2-fluorobenzaldehyde (100 mg, 0.449 mmol,79% yield) as a light yellow liquid. ¹H NMR (400 MHz, CDCl₃) δ 10.45 (s,1H), 7.63 (t, J=7.7 Hz, 1H), 7.45-7.31 (m, 1H), 2.08-2.00 (m, 3H).

33C. Preparation of1-(3-chloro-6-(1,1-difluoroethyl)-2-fluorophenyl)prop-2-en-1-one

1-(3-Chloro-6-(1,1-difluoroethyl)-2-fluorophenyl)prop-2-en-1-one wasprepared using a procedure analogous to that used for the preparation ofIntermediate 1 by replacing 3-chloro-2,6-difluorobenzaldehyde with3-chloro-6-(1,1-difluoroethyl)-2-fluorobenzaldehyde. ¹H NMR (400 MHz,CDCl₃) δ 7.52 (t, J=7.8 Hz, 1H), 7.29 (dd, J=8.4, 0.7 Hz, 1H), 6.64 (dd,J=17.6, 10.6 Hz, 1H), 6.22-6.16 (m, 1H), 6.03-5.94 (m, 1H), 1.91 (t,J=18.5 Hz, 3H).

33D. Preparation of(9R,13S)-13-{4-[3-chloro-6-(1,1-difluoroethyl)-2-fluorophenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[3-Chloro-6-(1,1-difluoroethyl)-2-fluorophenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onewas prepared according to the procedures described in Example 1 bysubstituting 1-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-onewith 1-(3-chloro-6-(1,1-difluoroethyl)-2-fluorophenyl)prop-2-en-1-one.¹H NMR (400 MHz, CD₃OD-d₄) 8.81 (d, J=5.3 Hz, 1H), 7.77 (s, 1H), 7.71(br. s., 1H), 7.65-7.58 (m, 1H), 7.57-7.52 (m, 1H), 7.45 (d, J=8.6 Hz,1H), 5.92 (s, 1H), 5.61 (d, J=9.5 Hz, 1H), 4.10 (s, 3H), 3.79-3.67 (m,2H), 2.71-2.58 (m, 3H), 2.25 (br. s., 1H), 2.06-1.87 (m, 5H), 1.71-1.56(m, 1H), 1.22 (br. s., 2H), 1.12 (d, J=6.8 Hz, 3H). MS(ESI) m/z: 572.2(M+H). Analytical HPLC (Method A): RT=10.48 min, purity=96%; Factor XIaKi=5.7 nM, Plasma Kallikrein Ki=50 nM.

Example 34 Preparation of(9R,13S)-3-[2-(tert-butoxy)ethyl]-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

34A. Preparation of 1-(2-(tert-butoxy)ethyl)-4-nitro-1H-pyrazole

DIAD (8.60 mL, 44.2 mmol) was added to a solution of 4-nitro-1H-pyrazole(5 g, 44.2 mmol), 2-(tert-butoxy)ethanol (5.23 g, 44.2 mmol), and PPh₃(11.60 g, 44.2 mmol) in THF (40 mL) and stirred at rt for 2 h. Thereaction mixture was then quenched with water and purified using silicagel chromatography to yield 1-(2-(tert-butoxy)ethyl)-4-nitro-1H-pyrazole(10.45 g, 44.1 mmol, 95% yield). ¹H NMR (400 MHz, CDCl₃) δ 8.24 (s, 1H),8.05 (s, 1H), 4.26 (t, J=5.1 Hz, 2H), 3.76-3.63 (m, 2H), 1.10 (s, 9H).

34B. Preparation of (S)-benzyl(1-(4-(1-(2-(tert-butoxy)ethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate

To a N₂ flushed pressure vial was added (S)-benzyl(1-(4-chloropyridin-2-yl)but-3-en-1-yl)carbamate (3.0 g, 9.47 mmol)prepared as (S)-tert-butyl(1-(4-chloropyridin-2-yl)but-3-en-1-yl)carbamate, described in Example1C, by replacing Boc₂O with Cbz-Cl, and1-(2-(tert-butoxy)ethyl)-4-nitro-1H-pyrazole (1.34 g, 6.31 mmol),di(adamant-1-yl)(butyl)phosphine (0.679 g, 1.894 mmol), PvOH (0.193 ml,1.894 mmol) and K₂CO₃ (2.62 g, 18.94 mmol). To the reaction mixture wasthen added DMF (18 mL) and the vial was purged with N₂ for 5 min. Tothis mixture was then added Pd(OAc)₂ (0.283 g, 1.263 mmol). The reactionmixture was again briefly purged with N₂. The vial was sealed and heatedin oil bath at 120° C. for 4 h. The reaction mixture was cooled to rtand partitioned between 10% aqueous LiCl (15 mL) and EtOAc (30 mL). Theaqueous layer was extracted with EtOAc (2×20 mL) and the combinedorganic layers were washed with brine (15 mL), dried over MgSO₄,filtered and concentrated. The crude product was then purified usingnormal phase chromatography to yield (S)-benzyl(1-(4-(1-(2-(tert-butoxy)ethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(2.2 g, 4.23 mmol, 67% yield) as a brown oil. MS(ESI) m/z: 494.2 (M+H)⁺.

34C. Preparation of (S)-benzyl(1-(4-(4-amino-1-(2-(tert-butoxy)ethyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate

A solution of (S)-benzyl(1-(4-(1-(2-(tert-butoxy)ethyl)-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(0.95 g, 1.925 mmol) in MeOH (10 mL) and AcOH (1.0 mL) was heated in oilbath to 40° C. To the above clear solution was then slowly added Zn(0.252 g, 3.85 mmol, in 3 portions (50:25:25%) and allowed to stir atthe same temperature for 5 min. The reaction mixture was monitored byLCMS and once reaction was completed, to the cooled reaction mixture wasthen added 1.0 g of K₂CO₃ (1 g for 1 mL AcOH) and 1.0 mL water, and wasthen stirred for 5 min. The reaction mixture was then filtered over apad of CELITE® and concentrated in vacuo to yield the crude product. Thecrude product was partitioned between EtOAc (40 mL) and sat aq NaHCO₃(20 mL). The organic layer was separated, dried over MgSO₄, filtered andconcentrated. The crude product was then purified using normal phasechromatography to yield (S)-benzyl(1-(4-(4-amino-1-(2-(tert-butoxy)ethyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(0.49 g, 1.004 mmol, 52% yield) as pale brown oil. MS(ESI) m/z: 464.5(M+H)⁺.

34D. Preparation of benzyl((S)-1-(4-(1-(2-(tert-butoxy)ethyl)-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate

To a N₂ flushed, 3-necked, 250 mL RBF was added (S)-benzyl(1-(4-(4-amino-1-(2-(tert-butoxy)ethyl)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(0.49 g, 1.057 mmol) and EtOAc (15 mL). The solution was cooled to −10°C. and (R)-2-methylbut-3-enoic acid, as prepared in Intermediate 6 (106mg, 1.057 mmol), pyridine (0.171 mL, 2.114 mmol) and T3P® (0.944 mL,1.586 mmol) were added. The cooling bath was removed and the solutionwas allowed to warm to rt and then stir over a period of 20 h. Water (20mL) and EtOAc (20 mL) were added and the mixture was stirred for 30 min.The organic phase was separated and the aqueous layer was extracted withEtOAc (20 mL). The combined organic extracts was washed with brine (15mL), dried over Na₂SO₄, filtered and concentrated in vacuo. Purificationby normal phase chromatography eluting with a gradient of hexanes/EtOAcgave benzyl((S)-1-(4-(1-(2-(tert-butoxy)ethyl)-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(0.35 g, 0.609 mmol, 58% yield). MS(ESI) m/z: 546.6 [M+H]⁺.

34E. Preparation of benzylN-[(9R,10E,13S)-3-[2-(tert-butoxy)ethyl]-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate

To a N₂ flushed, 250 mL, 3-necked, RBF was added a solution of benzyl((S)-1-(4-(1-(2-(tert-butoxy)ethyl)-4-((R)-2-methylbut-3-enamido)-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-yl)carbamate(350 mg, 0.641 mmol) in DCE (18 mL). The solution was sparged with Arfor 15 min. Second Generation Grubbs Catalyst (218 mg, 0.257 mmol) wasadded in one portion. The reaction mixture was heated in a microwave to120° C. for 30 min. After cooling to rt, the solvent was removed and theresidue was purified by normal phase chromatography eluting with agradient of DCM/MeOH to yield benzylN-[(9R,10E,13S)-3-[2-(tert-butoxy)ethyl]-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(140 mg, 0.243 mmol, 38% yield) as a tan solid. MS(ESI) m/z: 518.5[M+H]⁺.

34F. Preparation of(9R,13S)-13-amino-3-[2-(tert-butoxy)ethyl]-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

Pd on carbon (0.033 g, 0.031 mmol) was added to a 250 mL Parrhydrogenation flask containing a solution of benzylN-[(9R,10E,135)-3-[2-(tert-butoxy)ethyl]-9-methyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(160 mg, 0.309 mmol) in EtOH (10 mL). The flask was purged with N₂ andpressurized to 55 psi of H₂ and allowed to stir for 4 h. The reactionwas filtered through a pad of CELITE® and concentrated to yield(9R,13S)-13-amino-3-[2-(tert-butoxy)ethyl]-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(81 mg, 0.210 mmol, 68% yield) as a tan solid. MS(ESI) m/z: 386.5[M+H]⁺.

34G. Preparation of(9R,13S)-3-[2-(tert-Butoxy)ethyl]-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-3-[2-(tert-Butoxy)ethyl]-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate was prepared according to the procedures described inExample 1 by substituting1-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one with1-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one,Intermediate 4, to yield(9R,13S)-3-[2-(tert-butoxy)ethyl]-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (48 mg, 0.058 mmol, 27% yield). ¹H NMR (400 MHz, CD₃OD)δ 8.80 (d, J=5.5 Hz, 1H), 8.49-8.44 (m, 1H), 8.23 (d, J=5.5 Hz, 1H),7.82 (s, 1H), 7.68-7.53 (m, 4H), 5.86-5.79 (m, 1H), 5.48 (dd, J=12.8,3.5 Hz, 1H), 4.51-4.33 (m, 2H), 3.94-3.78 (m, 2H), 3.53-3.34 (m, 2H),2.58-2.46 (m, 1H), 2.26-2.14 (m, 3H), 2.02-1.83 (m, 2H), 1.66-1.51 (m,1H), 1.30 (br. s., 1H), 1.10 (d, J=6.8 Hz, 3H), 1.08-1.03 (m, 9H).MS(ESI) m/z: 677.5 [M+H]⁺. Analytical HPLC (Method A): RT=7.93 min,purity=>95.0%; Factor XIa Ki=1.1 nM, Plasma Kallikrein Ki=50 nM.

Example 35 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

To a solution of(9R,13S)-3-[2-(tert-butoxy)ethyl]-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (32 mg, 0.047 mmol)) in DCM was added TFA (2 mL) andthe reaction stirred at rt for 1 h. The reaction mixture was thenconcentrated in vacuo and purified using prep HPLC purification to yield(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3-(2-hydroxyethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (28.4 mg, 0.037 mmol, 78% yield). ¹H NMR (400 MHz,CD₃OD) δ 8.77 (d, J=5.3 Hz, 1H), 8.48 (s, 1H), 7.89 (dd, J=5.3, 1.3 Hz,1H), 7.70-7.58 (m, 6H), 5.86 (s, 1H), 5.56 (dd, J=12.8, 3.5 Hz, 1H),4.47-4.40 (m, 2H), 4.07-3.98 (m, 3H), 3.52 (t, J=6.8 Hz, 2H), 2.65-2.52(m, 1H), 2.49-2.36 (m, 1H), 2.34-2.11 (m, 2H), 2.01-1.82 (m, 2H),1.69-1.52 (m, 1H), 1.18 (br. s., 1H), 1.12 (d, J=7.0 Hz, 3H). MS(ESI)m/z: 621.5 [M+H]⁺. Analytical HPLC (Method A): RT=6.42 min,purity=>95.0%; Factor XIa Ki=0.82 nM, Plasma Kallikrein Ki=32 nM.

Example 36 Preparation of(9R,13S)-13-[4-(6-bromo-3-chloro-2-fluorophenyl)-6-oxo-1,2,3,6-tetrahydropyridin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-[4-(6-Bromo-3-chloro-2-fluorophenyl)-6-oxo-1,2,3,6-tetrahydropyridin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onewas prepared according to the procedures described in Example 1 bysubstituting,1-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one with1-(6-bromo-3-chloro-2-fluorophenyl)prop-2-en-1-one, Intermediate 12. ¹HNMR (400 MHz, CD₃OD) d 8.72 (d, J=5.1 Hz, 1H), 7.59 (s, 1H), 7.52-7.37(m, 4H), 5.93 (s, 1H), 5.65 (dd, J=12.7, 3.9 Hz, 1H), 4.04 (s, 3H),3.91-3.69 (m, 2H), 2.65-2.53 (m, 3H), 2.27-2.13 (m, 1H), 2.04-1.80 (m,2H), 1.66-1.51 (m, 1H), 1.37-1.17 (m, 1H), 1.05 (d, J=6.8 Hz, 3H),1.02-0.93 (m, 1H). MS(ESI) m/z: 586.0 (M+H). Analytical HPLC (Method A):RT=7.46 min, purity=>95%; Factor XIa Ki=1.7 nM, Plasma Kallikrein Ki=5nM.

Example 37 Preparation of(9R,13S)-13-[4-(2-bromo-5-chlorophenyl)-6-oxo-1,2,3,6-tetrahydropyridin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-[4-(2-Bromo-5-chlorophenyl)-6-oxo-1,2,3,6-tetrahydropyridin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (0.085 g, 20% yield) was prepared according to theprocedures described in Example 1M by replacing1-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one with1-(2-bromo-5-chlorophenyl)prop-2-en-1-one (0.15 g, 0.611 mmol),Intermediate 13. MS(ESI) m/z: 570.4 (M+2+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ8.79 (d, J=5.5 Hz, 1H), 7.80 (s, 1H), 7.75 (dd, J=5.5, 1.5 Hz, 1H), 7.63(d, J=8.6 Hz, 1H), 7.54 (s, 1H), 7.34 (d, J=2.6 Hz, 1H), 7.30 (dd,J=8.5, 2.5 Hz, 1H), 5.91 (t, J=1.2 Hz, 1H), 5.56 (dd, J=12.7, 3.9 Hz,1H), 4.08 (s, 3H), 3.72 (t, J=6.9 Hz, 2H), 2.73 (t, J=6.8 Hz, 2H),2.62-2.53 (m, 1H), 2.31-2.20 (m, 1H), 2.04-1.91 (m, 2H), 1.67-1.56 (m,1H), 1.27-1.16 (m, 2H), 1.10 (d, J=6.8 Hz, 3H). Analytical HPLC (MethodA): RT=7.44 min, 96.5% purity; Factor XIa Ki=4.7 nM, Plasma KallikreinKi=16 nM.

Example 38 Preparation of(9R,13S)-13-(4-{5-chloro-2-[1-(difluoromethyl)-1H-pyrazol-4-yl]phenyl}-6-oxo-1,2,3,6-tetrahydropyridin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

To a sealable tube was added(9R,13S)-13-[4-(2-bromo-5-chlorophenyl)-6-oxo-1,2,3,6-tetrahydropyridin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate (0.02 g, 0.029 mmol), prepared asdescribed in Example 37,1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(7.86 mg, 0.032 mmol), 3 M aq K₃PO₄ (0.039 ml, 0.117 mmol) and THF (1ml). Ar was bubbled through the reaction mixture for several min and(DtBPF)PdCl₂ (0.95 mg, 1.464 μmol) was added. The reaction was sealedand heated at 90° C. After 18 h, the reaction was cooled to rt andconcentrated. Purification by reverse phase chromatography afforded(9R,13S)-13-(4-{5-chloro-2-[1-(difluoromethyl)-1H-pyrazol-4-yl]phenyl}-6-oxo-1,2,3,6-tetrahydropyridin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (6.5 mg, 30% yield) as a white solid. MS(ESI) m/z:606.5 (M+H)⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.77 (br. s., 1H), 8.22 (s, 1H),7.83 (s, 1H), 7.78-7.66 (m, 2H), 7.52 (s, 1H), 7.50 (t, J=59.6 Hz, 1H),7.45-7.43 (m, 2H), 7.35 (t, J=1.2 Hz, 1H), 5.99 (s, 1H), 5.54 (d, J=9.4Hz, 1H), 4.07 (s, 3H), 3.49 (t, J=6.3 Hz, 2H), 2.60-2.52 (m, 1H), 2.37(t, J=6.9 Hz, 2H), 2.22-2.13 (m, 1H), 1.99-1.88 (m, 2H), 1.63-1.54 (m,1H), 1.23-1.14 (m, 2H), 1.09 (d, J=6.9 Hz, 3H). ¹⁹F NMR (376 MHz, CD₃OD)δ −77.60 (s), −96.03 (s). Analytical HPLC (Method A): RT=7.39 min, 98.5%purity; Factor XIa Ki=1.8 nM, Plasma Kallikrein Ki=120 nM.

Example 39 Preparation of4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,2,3,6-tetrahydropyridin-4-yl}-3-fluorobenzonitrile

4-Chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,2,3,6-tetrahydropyridin-4-yl}-3-fluorobenzonitrilewas prepared according to the procedures described in Example 19 bysubstituting,(9R,13S)-13-[4-(2-bromo-5-chlorophenyl)-6-oxo-1,2,3,6-tetrahydropyridin-1-yl]-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onewith(9R,13S)-13-[4-(6-bromo-3-chloro-2-fluorophenyl)-6-oxo-1,2,3,6-tetrahydropyridin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,Example 36. ¹H NMR (400 MHz, CD₃OD) δ 8.80 (d, J=5.5 Hz, 1H), 7.79 (s,1H), 7.75-7.63 (m, 3H), 7.54 (s, 1H), 6.19 (t, J=1.2 Hz, 1H), 5.59 (dd,J=12.5, 4.0 Hz, 1H), 4.09 (s, 3H), 3.81-3.71 (m, 2H), 2.84-2.69 (m, 2H),2.63-2.52 (m, 1H), 2.31-2.18 (m, 1H), 2.05-1.91 (m, 2H), 1.70-1.55 (m,1H), 1.21 (d, J=4.2 Hz, 2H), 1.09 (d, J=6.8 Hz, 3H). MS(ESI) m/z: 533.1(M+H). Analytical HPLC (Method A): RT=6.62 min, purity=>95%; Factor XIaKi=1.1 nM, Plasma Kallikrein Ki=120 nM.

Example 40 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,2,3,6-tetrahydropyridin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

40A. Preparation of5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)benzaldehyde

3,3,3-Trifluoroprop-1-yne gas was bubbled gently for 3 min into asuspension of 2-azido-5-chlorobenzaldehyde (160 mg, 0.881 mmol) and Cu₂O(14 mg, 0.098 mmol) in CH₃CN (6 ml). The reaction vessel was capped andthe reaction was stirred at rt overnight. The reaction was diluted withEtOAc and washed with sat NH₄Cl and brine. The organic layer was driedover MgSO₄, filtered and concentrated to give5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)benzaldehyde (241mg, 99% yield) as a beige solid. MS(ESI) m/z: 276.3 (M+H)⁺. ¹H NMR (400MHz, CDCl₃) δ 9.88 (s, 1H), 8.26 (d, J=0.9 Hz, 1H), 8.10 (d, J=2.4 Hz,1H), 7.78 (dd, J=8.4, 2.4 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H).

40B. Preparation of1-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-ol

To a solution of5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)benzaldehyde (241mg, 0.874 mmol) and THF (10 mL) at 0° C. was added dropwise 1.6 Mvinylmagnesium chloride in THF (1.137 mL, 1.137 mmol). The reaction wasstirred at 0° C. for 30 min and then at rt for 1 h. The reaction wasthen quenched with 1 N HCl. The reaction was partitioned between EtOAcand water and the layers were separated. The organic layer was washedwith brine, concentrated and purified on normal phase chromatography togive1-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-ol(224 mg, 84% yield) as a yellow oil. MS(ESI) m/z: 304.4 (M+H)⁺. ¹H NMR(400 MHz, CDCl₃) δ 8.18 (d, J=0.7 Hz, 1H), 7.72 (d, J=2.2 Hz, 1H), 7.47(dd, J=8.4, 2.4 Hz, 1H), 7.32 (d, J=8.4 Hz, 1H), 5.87 (ddd, J=17.3,10.3, 5.4 Hz, 1H), 5.20 (dt, J=6.0, 1.2 Hz, 1H), 5.18-5.14 (m, 1H), 5.11(d, J=4.0 Hz, 1H), 2.82 (br. s., 1H).

40C. Preparation of1-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one

To a solution of1-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-ol (124 mg, 0.408 mmol) in acetone (5 mL) at 0° C. was addeddropwise Jones reagent (0.16 mL, 0.408 mmol) until a brown colorpersisted. The reaction mixture was quenched with IPA, diluted withEtOAc and basified with sat NaHCO₃ to pH 8. The organic layer wasseparated and the aqueous layer was extracted with EtOAc (2×). Thecombined organic layers were washed with brine, concentrated, and thenpurified on normal phase chromatography to give1-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one(112 mg, 91% yield) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 8.11 (s,1H), 7.71-7.66 (m, 1H), 7.65 (d, J=2.2 Hz, 1H), 7.54 (d, J=8.4 Hz, 1H),6.41 (dd, J=17.5, 10.7 Hz, 1H), 6.10-5.91 (m, 2H). MS(ESI) m/z: 302.3(M+H)⁺.

40D. Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,2,3,6-tetrahydropyridin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,2,3,6-tetrahydropyridin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (14 mg, 36% yield) was prepared according to theprocedures described in Example 1 by replacing1-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one with1-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one.¹H NMR (400 MHz, CD₃OD) δ 8.93 (d, J=0.7 Hz, 1H), 8.72 (br. s., 1H),7.69-7.55 (m, 5H), 7.50 (s, 1H), 5.80 (s, 1H), 5.52 (d, J=11.9 Hz, 1H),4.05 (s, 3H), 3.56-3.42 (m, 2H), 2.60-2.48 (m, 1H), 2.24 (t, J=6.6 Hz,2H), 2.13 (m, 1H), 2.03-1.78 (m, 2H), 1.62-1.51 (m, 1H), 1.18 (m., 1H),1.07 (d, J=6.8 Hz, 3H). MS(ESI) m/z: 625.1 (M+H). Analytical HPLC(Method A): RT=7.44 min, purity=97%; Factor XIa Ki=0.1 nM, PlasmaKallikrein Ki=6 nM.

Example 41 Preparation of(9R,13S)-13-(4-{3-chloro-6-[1-(difluoromethyl)-1H-pyrazol-4-yl]-2-fluorophenyl}-6-oxo-1,2,3,6-tetrahydropyridin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-(4-{3-Chloro-6-[1-(difluoromethyl)-1H-pyrazol-4-yl]-2-fluorophenyl}-6-oxo-1,2,3,6-tetrahydropyridin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (9.5 mg, 38% yield) was prepared according to theprocedure described in Example 38 by replacing(9R,13S)-13-[4-(2-bromo-5-chlorophenyl)-6-oxo-1,2,3,6-tetrahydropyridin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate with(9R,13S)-13-[4-(6-bromo-3-chloro-2-fluorophenyl)-6-oxo-1,2,3,6-tetrahydropyridin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.02 g, 0.034 mmol), prepared as described in Example 36. MS(ESI) m/z:624.5 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.73 (d, J=5.1 Hz, 1H), 8.24 (s,1H), 7.83 (s, 1H), 7.60 (s, 1H), 7.56-7.52 (m, 2H), 7.50 (s, 1H), 7.49(t, J=59.0 Hz, 1H), 7.30 (dd, J=8.4, 1.3 Hz, 1H), 5.96 (s, 1H), 5.59(dd, J=12.8, 3.7 Hz, 1H), 4.05 (s, 3H), 3.64-3.49 (m, 2H), 2.62-2.51 (m,1H), 2.42 (t, J=6.7 Hz, 2H), 2.22-2.11 (m, 1H), 2.01-1.83 (m, 2H),1.64-1.53 (m, 1H), 1.27-1.03 (m, 5H). ¹⁹F NMR (376 MHz, CD₃OD) δ −77.45(s), −96.21 (s), −117.57 (s). Analytical HPLC (Method A): RT=7.47 min,100% purity. Factor XIa Ki=1 nM, Plasma Kallikrein Ki=34 nM.

Example 42 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,2,3,6-tetrahydropyridin-1-yl)-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,2,3,6-tetrahydropyridin-1-yl)-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (21 mg, 41% yield) was prepared according to theprocedures described in Example 1 by using1-(5-chloro-2-(4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one,prepared as described in Example 40C, and(9R,13S)-13-amino-3-(²H₃)methyl-9-methyl-3,4,7,18-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,prepared as described in Example 18. ¹H NMR (400 MHz, CD₃OD-d₄) δ 8.94(d, J=0.7 Hz, 1H), 8.77 (br. s., 1H), 7.75 (br. s., 2H), 7.69-7.59 (m,4H), 7.52 (s, 1H), 5.79 (s, 1H), 5.47 (d, J=10.3 Hz, 1H), 3.50 (t, J=6.6Hz, 2H), 2.55 (ddd, J=9.3, 6.5, 3.3 Hz, 1H), 2.27 (t, J=6.7 Hz, 2H),2.22-2.11 (m, 1H), 1.99-1.83 (m, 2H), 1.64-1.52 (m, 1H), 1.17 (br. s.,2H), 1.08 (d, J=6.8 Hz, 3H) MS(ESI) m/z: 628.2 (M+H). Analytical HPLC(Method A): RT=7.43 min, purity=99%; Factor XIa Ki=0.1 nM, PlasmaKallikrein Ki=7 nM.

Example 43 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3,9-dimethyl-3,4,7,18-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

43A. Preparation of(S)—N-[(1E)-(6-chloropyridin-2-yl)methylidene]-2-methylpropane-2-sulfinamide

To a solution of (S)-2-methylpropane-2-sulfinamide (1.712 g, 14.13 mmol)in DCM (61.4 mL) was added sequentially Cs₂CO₃ (6.91 g, 21.19 mmol) and6-chloropicolinaldehyde (2.0 g, 14.13 mmol). The resulting whitesuspension was stirred at rt. After 17 h, the reaction was stopped andfiltered. The filtrate was diluted with EtOAc (100 ml) and washed withbrine (50 mL×3). The organic layer was dried over MgSO₄, filtered andconcentrated to give(S)—N-[(1E)-(6-chloropyridin-2-yl)methylidene]-2-methylpropane-2-sulfinamide(3.58 g, 104%) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 8.65 (s, 1H),7.99-7.94 (m, 1H), 7.79 (t, J=7.7 Hz, 1H), 7.45 (dd, J=7.9, 0.7 Hz, 1H),1.28 (s, 10H).

43B. Preparationof(S)—N-[(1S)-1-(6-chloropyridin-2-yl)but-3-en-1-yl]-2-methylpropane-2-sulfinamide,and 43C. Preparation of(S)—N-[(1R)-1-(6-chloropyridin-2-yl)but-3-en-1-yl]-2-methylpropane-2-sulfinamide

To a mixture of(S)—N-[(1E)-(6-chloropyridin-2-yl)methylidene]-2-methylpropane-2-sulfinamide(1.73 g, 7.07 mmol) and In (0.92 g, 10.60 mmol) in THF (17.7 ml) wasslowly added 3-bromoprop-1-ene (0.92 g, 10.60 mmol). The reaction washeated at 60° C. overnight. The reaction mixture was cooled to rt,filtered through CELITE® and the filtrate was concentrated. Theresulting residue was purified by normal phase chromatography, usinghexanes and EtOAc, which gave a 5.6:1 of(S)—N-[(1S)-1-(6-chloropyridin-2-yl)but-3-en-1-yl]-2-methylpropane-2-sulfinamide:(S)—N-[(1R)-1-(6-chloropyridin-2-yl)but-3-en-1-yl]-2-methylpropane-2-sulfinamide(2.42 g, 58%) as the major product and as a brown semi-solid. MS(ESI)m/z: 287.4 (M+H)⁺.

43D. Preparation of(S)-2-methyl-N-[(1R)-1-[6-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl]but-3-en-1-yl]propane-2-sulfinamide(Diastereomer A), and 43E. Preparation of(S)-2-methyl-N-[(1S)-1-[6-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl]but-3-en-1-yl]propane-2-sulfinamide(Diastereomer B)

To a N₂ flushed pressure vial was added 5.6:1 of(S)—N-[(1S)-1-(6-chloropyridin-2-yl)but-3-en-1-yl]-2-methylpropane-2-sulfinamide:(S)—N-[(1R)-1-(6-chloropyridin-2-yl)but-3-en-1-yl]-2-methylpropane-2-sulfinamide(2.18 g, 7.60 mmol), 1-methyl-4-nitro-1H-pyrazole (0.966 g, 7.60 mmol),prepared as described in Example 1D, di(adamant-1-yl)(butyl)phosphine(0.954 g, 2.66 mmol), PvOH (0.300 ml, 2.58 mmol), K₂CO₃ (3.62 g, 26.2mmol), Pd(OAc)₂ (0.341 g, 1.52 mmol) and DMF (15.2 mL). The vial waspurged with Ar. The vial was sealed and heated in oil bath at 120° C.overnight. The reaction mixture was cooled to rt, partitioned betweenwater and EtOAc, and the layers were separated. The aqueous layer wasextracted with EtOAc (3×) and the organic layers were combined andconcentrated. The crude product was purified using normal phasechromatography followed a second purification by reverse phasechromatography to give(S)-2-methyl-N-[(1R)-1-[6-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl]but-3-en-1-yl]propane-2-sulfinamide(Diastereomer A) (0.275 g, 13%) MS(ESI) m/z: 274.4 (M+H)⁺. And(S)-2-methyl-N-[(1S)-1-[6-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl]but-3-en-1-yl]propane-2-sulfinamide(Diastereomer B) (1.2 g, 57%) MS(ESI) m/z: 274.4 (M+H)⁺.

43F. Preparation of tert-butylN-[(1S)-1-[6-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl]but-3-en-1-yl]carbamate

(1S)-1-(6-(1-Methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl)but-3-en-1-amine(Diastereomer B) (1.2 g, 3.18 mmol) was dissolved in MeOH (5 mL) anddioxane (25 ml). 4 N HCl in dioxane (4.8 ml, 19.1 mmol) was added. Thereaction was stirred at rt for 3 h and then the reaction wasconcentrated. The residue was coevaporated with toluene, dissolved inDCM (40 mL), and cooled to 0° C. TEA (4.43 mL, 31.8 mmol) was addedfollowed by BOC₂O (0.738 mL, 3.18 mmol). The reaction was stirred at 0°C. for 15 min and then the reaction was allowed to warm to rt. After 2h, the reaction was diluted with DCM, washed with sat NaHCO₃, brine, andconcentrated. Purification by normal phase chromatography gavetert-butylN-[(1S)-1-[6-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl]but-3-en-1-yl]carbamate(393 mg, 33% yield) as an orange oil. MS(ESI) m/z: 374.5 (M+H)⁺. ¹H NMR(400 MHz, CDCl₃) δ 8.19 (s, 1H), 7.84 (t, J=7.8 Hz, 1H), 7.55 (d, J=7.7Hz, 1H), 7.38 (d, J=7.7 Hz, 1H), 5.77-5.58 (m, 1H), 5.40 (br. s., 1H),5.13-5.01 (m, 2H), 4.92 (d, J=6.8 Hz, 1H), 3.86 (s, 3H), 2.71-2.51 (m,2H), 1.43 (s, 9H).

43G. Preparation of tert-butylN-[(1S)-1-[6-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl]but-3-en-1-yl]carbamate

To a solution of tert-butylN-[(1S)-1-[6-(1-methyl-4-nitro-1H-pyrazol-5-yl)pyridin-2-yl]but-3-en-1-yl]carbamate (393 mg, 1.05 mmol) in MeOH (6.4mL) was added AcOH (0.64 mL). The reaction flask was put in a preheatedbath at 45° C. then Zn powder (206 mg, 3.16 mmol) was added portionwise.After 1 h, additional Zn (198 mg) was added. Upon completion of thereaction, the mixture was cooled to rt, partitioned between DCM and satNaHCO₃, and the layers were separated. The aqueous layer was extractedwith DCM (2×). The organic layers were combined and washed with brine,dried over MgSO₄, filtered and concentrated to give tert-butylN-[(1S)-1-[6-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl]but-3-en-1-yl]carbamate (343 mg, 95% yield) as a yellowfoam. MS(ESI) m/z: 344.5 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.74 (t,J=7.8 Hz, 1H), 7.39 (dd, J=7.8, 0.8 Hz, 1H), 7.25-7.18 (m, 1H), 7.14 (d,J=7.7 Hz, 1H), 5.70 (ddt, J=17.1, 10.2, 7.0 Hz, 1H), 5.46 (d, J=6.8 Hz,1H), 5.13-4.99 (m, 2H), 4.89 (d, J=6.8 Hz, 1H), 4.01 (s, 3H), 2.71-2.53(m, 2H), 1.49-1.30 (m, 9H).

43H. Preparation of tert-butylN-[(1S)-1-(6-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl)}pyridin-2-yl)but-3-en-1-yl]carbamate

To tert-butylN-[(1S)-1-[6-(4-amino-1-methyl-1H-pyrazol-5-yl)pyridin-2-yl]but-3-en-1-yl]carbamate(343 mg, 0.999 mmol) in EtOAc (3.33 ml) was added a solution of(R)-2-methylbut-3-enoic acid (0.150 g, 1.498 mmol), Intermediate 6, inEtOAc (1 ml). The mixture was cooled to 0° C. and pyridine (0.24 ml, 3.0mmol) was added, followed by the addition of a solution of 50% T3P® inEtOAc (1.19 ml, 1.50 mmol). After 2 h, the reaction was partitionedbetween sat NaHCO₃ and EtOAc, and the layers were separated. The aqueouslayer was extracted with EtOAc (2×). The organic layers were combinedand washed with brine and then concentrated. Purification by normalphase chromatography gave tert-butylN-[(1S)-1-(6-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl}pyridin-2-yl)but-3-en-1-yl]carbamate(360 mg, 85%) as a yellow solid. MS(ESI) m/z: 426.5 (M+H)⁺. ¹H NMR (400MHz, CDCl₃) δ 9.35 (br. s., 1H), 8.30 (s, 1H), 7.82 (t, J=7.8 Hz, 1H),7.40 (d, J=7.9 Hz, 1H), 7.32-7.19 (m, 1H), 6.01 (ddd, J=17.4, 10.0, 7.6Hz, 1H), 5.78-5.57 (m, 1H), 5.35-5.04 (m, 5H), 4.91 (br. s., 1H), 4.06(s, 3H), 3.26-3.06 (m, 1H), 2.81-2.54 (m, 2H), 1.54-1.30 (m, 12H).

43I. Preparation of tert-butylN-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,18-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate

A solution of tert-butylN-[(1S)-1-(6-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl}pyridin-2-yl)but-3-en-1-yl]carbamate (140 mg, 0.329 mmol) in EtOAc (25 ml) was purgedwith Ar for 20 min. Second Generation Grubbs Catalyst (0.112 g, 0.132mmol) was added and the reaction mixture heated at 80° C. overnight. Thereaction mixture was cooled to rt and concentrated. Purification bynormal phase chromatography and then by reverse phase chromatography wasdone. The fractions containing the desired product were made basic (pH˜8) with sat NaHCO₃ and then concentrated. The residue was partitionedbetween water and EtOAc and the layers were separated. The aqueous layerwas extracted with DCM (3×) and EtOAc (3×). The organic layers werecombined and washed with brine, dried MgSO₄, filtered and concentratedto give tert-butylN-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,18-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(96 mg, 66% yield). MS(ESI) m/z: 398.2 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ11.12 (br. s., 1H), 8.08 (s, 1H), 7.84 (t, J=7.9 Hz, 1H), 7.39 (dd,J=7.9, 0.7 Hz, 1H), 7.32-7.24 (m, 1H), 5.98-5.83 (m, 1H), 5.55 (dd,J=15.7, 7.4 Hz, 1H), 5.41 (d, J=6.6 Hz, 1H), 5.04 (m, 1H), 4.10-4.03 (m,3H), 3.15 (quin, J=7.3 Hz, 1H), 2.84-2.56 (m, 2H), 1.51-1.32 (m, 12H).

43J. Preparation of tert-butylN-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,18-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate,and 43K. Preparation of tert-ButylN-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,18-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-2(6),4-dien-13-yl]carbamate

A solution of tert-butylN-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7,18-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(0.096 g, 0.024 mmol) in EtOH (4 ml) was hydrogenated at 20 psi H₂ inthe presence of PtO₂ (20 mg) for 20 h. The mixture was filtered, washingwith MeOH and EtOAc. The filtrate was concentrated and then purified byreverse phase chromatography to give, following neutralization of thefractions and extraction,tert-butyl-N-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,18-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-2(6),4-dien-13-yl]carbamate(20 mg, 20.4% yield), MS(ESI) m/z: 406.2 (M+H)+; and tert-butylN-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,18-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(68 mg, 70.5% yield), MS(ESI) m/z: 400.2 (M+H)⁺.

43L. Preparation of(9R,13S)-13-amino-3,9-dimethyl-3,4,7,18-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

To a solution of tert-butylN-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,18-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(0.035 g, 0.088 mmol) in DCM (0.5 ml) was added TFA (0.2 mL, 2.60 mmol).After stirring for 1 h, the reaction mixture was concentrated todryness, and coevaporated with CH₃CN. The residue was neutralized bydissolving in MeOH, passing through NaHCO₃ cartridge (StratoSpheres SPE;500 mg, 0.90 mmol loading), and concentrating the filtrate to give(9R,13S)-13-amino-3,9-dimethyl-3,4,7,18-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(15 mg, 57% yield) as clear glass which was used without furtherpurification. MS(ESI) m/z: 300.5 (M+H)⁺.

43M. Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3,9-dimethyl-3,4,7,18-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3,9-dimethyl-3,4,7,18-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(7 mg, 32% yield) was prepared according to the procedures described inExample 1 by using1-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one,prepared as described in Intermediate 4, and(9R,13S)-13-amino-3,9-dimethyl-3,4,7,18-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one.MS(ESI) m/z: 591.2 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.43 (s, 1H), 7.95(t, J=7.8 Hz, 1H), 7.66-7.60 (m, 3H), 7.58-7.53 (m, 2H), 7.34 (d, J=7.7Hz, 1H), 5.83 (s, 1H), 5.68 (dd, J=11.1, 1.9 Hz, 1H), 4.05 (s, 3H), 2.93(ddd, J=13.1, 7.8, 5.5 Hz, 1H), 2.65-2.52 (m, 1H), 2.51-2.39 (m, 1H),2.19-2.09 (m, 1H), 2.02-1.91 (m, 1H), 1.83-1.64 (m, 3H), 1.60-1.49 (m,1H), 1.32-1.19 (m, 1H), 1.16 (d, J=6.8 Hz, 3H). Analytical HPLC (MethodA): RT=8.46 min, purity=99.6%; Factor XIa Ki=4.1 nM, Plasma KallikreinKi=110 nM.

Example 44 Preparation of(9R,13S)-13-[4-(3,6-dichloro-2-fluorophenyl)-2-oxo-1,2-dihydropyridin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

To a sealable tube containing(9R,13S)-13-[4-(3,6-dichloro-2-fluorophenyl)-6-oxo-1,2,3,6-tetrahydropyridin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one),prepared as described in Example 24, CuI (0.368 mg, 1.935 μmol) in DMSO(1 ml) was added 3-iodopyridine (7.93 mg, 0.039 mmol) and Cs₂CO₃ (0.025g, 0.077 mmol). The reaction mixture was purged with Ar (3×), thenwarmed to 80° C. After 44 h, the reaction was cooled to rt. Purificationby reverse phase chromatography afforded(9R,13S)-13-[4-(3,6-dichloro-2-fluorophenyl)-2-oxo-1,2-dihydropyridin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (1.91 mg, 15% yield) as a white solid. MS(ESI) m/z:540.1 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.74 (d, J=5.1 Hz, 1H), 8.23 (d,J=7.0 Hz, 1H), 7.75 (s, 1H), 7.59-7.50 (m, 3H), 7.39 (dd, J=8.8, 1.5 Hz,1H), 6.55 (d, J=2.0 Hz, 1H), 6.42 (dd, J=7.0, 1.5 Hz, 1H), 6.17 (dd,J=12.8, 4.2 Hz, 1H), 4.06 (s, 3H), 2.74-2.64 (m, 1H), 2.38-2.26 (m, 1H),2.15-1.99 (m, 2H), 1.70-1.58 (m, 1H), 1.52-1.39 (m, 1H), 1.03 (d, J=7.0Hz, 3H), 0.89-0.72 (m, 1H). Analytical HPLC (Method A): RT=7.43 min,97.9% purity; Factor XIa Ki=2.2 nM, Plasma Kallikrein Ki=5.7 nM.

Example 45 Preparation of(9R,13S)-13-[4-(3-chloro-2,6-difluorophenyl)-6-oxo-1,2,3,6-tetrahydropyridin-1-yl]-3-ethyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-[4-(3-Chloro-2,6-difluorophenyl)-6-oxo-1,2,3,6-tetrahydropyridin-1-yl]-3-ethyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onewas prepared according to the procedures described in Example 1 by using1-(3-chloro-2,6-difluorophenyl)prop-2-en-1-one, Intermediate 1, and1-ethyl-4-nitro-1H-pyrazole, Intermediate 8. ¹H NMR (400 MHz, CD₃OD) δ8.84 (d, J=5.5 Hz, 1H), 7.86 (s, 1H), 7.76 (dd, J=5.7, 1.5 Hz, 1H), 7.61(s, 1H), 7.56 (td, J=8.7, 5.5 Hz, 1H), 7.12 (td, J=9.2, 1.8 Hz, 1H),6.13 (s, 1H), 5.56 (dd, J=12.5, 4.0 Hz, 1H), 4.43 (q, J=7.1 Hz, 2H),3.74 (t, J=6.8 Hz, 2H), 2.85-2.69 (m, 2H), 2.65-2.54 (m, 1H), 2.38-2.20(m, 1H), 2.10-1.88 (m, 2H), 1.71-1.58 (m, 1H), 1.53 (t, J=7.3 Hz, 3H),1.22 (br. s., 2H), 1.12 (d, J=6.8 Hz, 3H). MS(ESI) m/z: 540.2 (M+H)⁺.Analytical HPLC (Method A): RT=11.04 min, purity=97%; Factor XIa Ki=13nM, Plasma Kallikrein Ki=54 nM.

Example 46 Preparation of(9R,13S)-13-[4-(6-acetyl-3-chloro-2-fluorophenyl)-6-oxo-1,2,3,6-tetrahydropyridin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

A mixture of(9R,13S)-13-[4-(6-bromo-3-chloro-2-fluorophenyl)-6-oxo-1,2,3,6-tetrahydropyridin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(18 mg, 0.031 mmol), tributyl(1-ethoxyvinyl)stannane (20.72 μl, 0.061mmol) and Pd(PPh₃)₂Cl₂ (2.153 mg, 3.07 μmol) in toluene (767 μl) wasdegassed and heated at 110° C. overnight. The solvent was removed and 2ml of a 1:1 mixture of 1 N HCl and THF was added. The mixture wasstirred at rt for 0.5 h and was concentrated. The crude product was thenpurified using reverse phase HPLC to afford(9R,13S)-13-[4-(6-acetyl-3-chloro-2-fluorophenyl)-6-oxo-1,2,3,6-tetrahydropyridin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (9.6 mg, 46%). ¹H NMR (500 MHz, DMSO-d₆) δ 9.24 (s,1H), 8.74 (d, J=5.2 Hz, 1H), 7.85-7.73 (m, 2H), 7.59-7.44 (m, 3H),7.27-7.00 (m, 1H), 5.71 (s, 1H), 5.60 (d, J=8.9 Hz, 1H), 4.02 (s, 3H),3.88 (br. s., 1H), 3.70 (d, J=5.5 Hz, 1H), 3.51-3.38 (m, 5H), 2.17-1.93(m, 2H), 1.69 (br. s., 1H), 1.48 (br. s., 1H), 1.28-1.10 (m, 1H), 0.93(d, J=6.7 Hz, 3H), 0.66 (br. s., 1H). MS(ESI) m/z: 550.4 (M+H).Analytical HPLC (Method C): RT=1.40 min, purity=>95%; Factor XIa Ki=3.5nM, Plasma Kallikrein Ki=46 nM.

Example 47 Preparation of(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(trifluoromethyl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-9-methyl-4-(pyrimidin-5-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-one

47A. Preparation of(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(trifluoromethyl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one trifluoroacetate

(9R,13S)-13-{4-[3-Chloro-2-fluoro-6-(trifluoromethyl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (262 mg, 0.387 mmol, 65% yield) was prepared accordingto the procedures described in Example 1 by substituting,1-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one with1-(3-chloro-2-fluoro-6-(trifluoromethyl)phenyl)prop-2-en-1-one,Intermediate 2. ¹H NMR (500 MHz, DMSO-d₆) δ 9.25 (s, 1H), 8.59 (d, J=4.3Hz, 1H), 7.91-7.79 (m, 2H), 7.74-7.65 (m, 2H), 7.44 (d, J=4.9 Hz, 1H),7.26-6.96 (m, 1H), 5.91 (s, 1H), 5.65 (d, J=8.9 Hz, 1H), 3.91-3.81 (m,1H), 3.60 (br. s., 1H), 2.65 (br. s., 2H), 2.20-1.97 (m, 2H), 1.76 (br.s., 1H), 1.51 (br. s., 1H), 1.31 (br. s., 1H), 0.95 (d, J=7.0 Hz, 3H),0.81 (br. s., 1H). MS(ESI) m/z: 562.3 [M+H]⁺. Analytical HPLC (MethodB): RT=1.72 min, purity=100.0%.

47B. Preparation of(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(trifluoromethyl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-9-methyl-4-(pyrimidin-5-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-{4-[3-Chloro-2-fluoro-6-(trifluoromethyl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-9-methyl-4-(pyrimidin-5-yl)-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2,5,14,16-pentaen-8-onetrifluoroacetate (7.5 mg, 9.85 μmol, 18% yield) was prepared accordingto the procedures described in Example 11 by substituting(2-bromoethoxy)(tert-butyl)dimethylsilane with 5-iodopyrimidine. ¹H NMR(500 MHz, DMSO-d₆) δ 9.58 (s, 1H), 9.39 (s, 2H), 9.19 (s, 1H), 8.80 (s,1H), 8.68 (d, J=4.9 Hz, 1H), 7.85 (t, J=7.8 Hz, 1H), 7.76 (s, 1H), 7.70(d, J=8.5 Hz, 1H), 7.60 (d, J=4.3 Hz, 1H), 7.26-6.97 (m, 1H), 5.92 (s,1H), 5.71 (d, J=8.8 Hz, 1H), 3.97 (br. s., 1H), 3.67 (br. s., 1H),3.44-3.36 (m, 1H), 2.73 (br. s., 1H), 2.19 (br. s., 1H), 2.06 (br. s.,1H), 1.76 (br. s., 1H), 1.56 (br. s., 1H), 1.34 (br. s., 1H), 0.97 (d,J=6.7 Hz, 3H), 0.69 (br. s., 1H). MS(ESI) m/z: 640.1 [M+H]⁺. AnalyticalHPLC (Method B): RT=1.84 min, purity=99.0%; Factor XIa Ki=5.4 nM, PlasmaKallikrein Ki=13 nM.

Example 48 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

48A. Preparation of tert-butylN-[(1S)-1-[3-(1-methyl-4-nitro-1H-pyrazol-5-yl)phenyl]but-3-en-1-yl]carbamate

To tert-butyl N-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]carbamate (2 g,6.13 mmol), 1-methyl-4-nitro-1H-pyrazole (0.779 g, 6.13 mmol),di(adamantan-1-yl)(butyl) phosphine (0.659 g, 1.839 mmol), pivalic acid(0.213 ml, 1.839 mmol), K₂CO₃ (2.54 g, 18.39 mmol) was added DMF (9 ml).The mixture was degassed with Ar for 10 min. Pd(OAc)₂ (0.275 g, 1.226mmol) was added and the reaction was heated in oil bath at 120° C. for15 h. The reaction was partitioned between water (50 ml) and EtOAc (50ml) and solution was filtered through paper and the layers wereseparated. The aqueous layer was extracted with EtOAc (2×50 ml). Thecombined organic layers were washed with brine (50 ml), dried overMgSO₄, filtered and concentrated. The residue was purified by normalphase chromatography using hexanes and EtOAc as eluents to afford(S)-tert-butyl(1-(3-(1-methyl-4-nitro-1H-pyrazol-5-yl)phenyl)but-3-en-1-yl)carbamate(1.186 g, 3.18 mmol, 51.9% yield) as a yellow oil. MS(ESI) m/z: 371.1(M−H)⁺.

48B. Preparation of tert-butylN-[(1S)-1-[3-(4-amino-1-methyl-1H-pyrazol-5-yl)phenyl]but-3-en-1-yl]carbamate

To tert-butylN-[(1S)-1-[3-(1-methyl-4-nitro-1H-pyrazol-5-yl)phenyl]but-3-en-1-yl]carbamate(0.097 g, 0.260 mmol) in acetone (5 ml)/water (1 ml), cooled to 0° C.,was added NH₄Cl (0.070 g, 1.302 mmol) and Zn (0.170 g, 2.60 mmol). Theice bath was removed. After 3 h, the reaction was filtered and thefiltrate was partitioned between water (10 ml) and EtOAc (30 ml). Theaqueous layer was extracted with EtOAc (2×20 ml). The combined organiclayers were washed with brine (10 ml), dried over MgSO₄, filtered andconcentrated. The residue was purified by normal phase chromatographyusing DCM and 0-10% MeOH as eluents to afford tert-butylN-[(1S)-1-[3-(4-amino-1-methyl-1H-pyrazol-5-yl)phenyl]but-3-en-1-yl]carbamate(76.6 mg, 86%). MS(ESI) m/z: 343.2 (M+H)⁺.

48C. Preparation of tert-butylN-[(1S)-1-(3-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl}phenyl)but-3-en-1-yl]carbamate

To tert-butylN-[(1S)-1-[3-(4-amino-1-methyl-1H-pyrazol-5-yl)phenyl]but-3-en-1-yl]carbamate(0.076 g, 0.222 mmol) in EtOAc (0.58 ml) was added(R)-2-methylbut-3-enoic acid (0.027 g, 0.266 mmol), Intermediate 6, in0.3 ml EtOAc. The mixture was cooled to 0° C. and Hunig's Base (0.116ml, 0.666 mmol) followed by a solution of 50% T3P® in EtOAc (0.264 ml,0.444 mmol) were added. After 3 h, the reaction was partitioned with satNaHCO₃ (5 ml) and EtOAc (5 ml). The aqueous layer was extracted withEtOAc (2×10 ml). The combined organic layers were washed with brine (5ml), dried over MgSO₄, filtered and concentrated. The residue waspurified by normal phase chromatography using hexanes and EtOAc aseluents to afford (69 mg, 73%) of tert-butylN-[(1S)-1-(3-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl}phenyl)but-3-en-1-yl]carbamateas a yellow oil. MS(ESI) m/z: 425.2 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ8.04 (s, 1H), 7.52-7.45 (m, 1H), 7.37 (d, J=7.9 Hz, 1H), 7.26-7.18 (m,2H), 7.05 (br. s., 1H), 5.96-5.85 (m, 1H), 5.69 (ddt, J=17.0, 10.1, 7.0Hz, 1H), 5.21-5.09 (m, 4H), 4.95 (br. s., 1H), 4.77 (br. s., 1H), 3.76(s, 3H), 3.07 (quin, J=7.2 Hz, 1H), 2.61-2.48 (m, 2H), 1.45-1.38 (m,9H), 1.30 (d, J=7.0 Hz, 3H).

48D. Preparation of tert-butylN-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate

A solution of tert-butylN-[(1S)-1-(3-{1-methyl-4-[(2R)-2-methylbut-3-enamido]-1H-pyrazol-5-yl}phenyl)but-3-en-1-yl]carbamate(0.069 g, 0.163 mmol) in degassed DCE (10 ml) was heated to 120° C. for30 min in a microwave in the presence of Second Generation GrubbsCatalyst (0.055 g, 0.065 mmol). The reaction mixture was directlypurified by normal phase chromatography twice using hexanes and EtOAc aseluents to afford desired tert-butylN-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(33 mg, 51.2%) as a dark solid. MS(ESI) m/z: 397.1 (M+H)⁺. ¹H NMR (400MHz, CDCl₃) δ 7.61-7.52 (m, 1H), 7.46-7.40 (m, 1H), 7.33-7.25 (m, 1H),7.20 (d, J=7.5 Hz, 1H), 6.93 (br. s., 1H), 6.83 (s, 1H), 5.63 (ddd,J=15.1, 9.4, 5.6 Hz, 1H), 5.18 (br. s., 1H), 4.89 (dd, J=15.2, 8.8 Hz,1H), 4.69 (br. s., 1H), 3.93-3.86 (m, 3H), 3.09-2.99 (m, 1H), 2.69-2.58(m, 1H), 2.17-2.08 (m, 1H), 1.53-1.32 (m, 9H), 1.18 (d, J=6.8 Hz, 3H).

48E. Preparation of tert-butylN-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate

A solution of tert-butylN-[(9R,10E,13S)-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(0.089 g, 0.224 mmol) in EtOH (5 ml) was hydrogenated under a H₂atmosphere at 55 psi for 3 h. The reaction mixture was filtered throughsmall plug of CELITE® and rinsed with EtOH/MeOH/DCM to give tert-butylN-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(89 mg, 99%) as a white solid. MS(ESI) m/z: 399.4 (M+H)⁺. ¹H NMR (400MHz CDCl₃) δ 7.53-7.43 (m, 2H), 7.43-7.36 (m, 1H), 7.29 (s, 1H), 6.44(s, 1H), 4.90 (br. s., 1H), 4.68 (br. s., 1H), 3.98 (s, 3H), 2.44 (br.s., 1H), 1.93 (d, J=7.7 Hz, 1H), 1.85-1.63 (m, 2H), 1.42 (br. s., 9H),1.28-1.19 (m, 2H), 1.07 (d, J=6.8 Hz, 3H), 0.96 (br. s., 1H).

48F. Preparation of(9R,13S)-13-amino-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one, hydrochloride

tert-ButylN-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(88 mg, 0.221 mmol) was deprotected with 4 N HCl in dioxane (3 ml) for 5h. The reaction was concentrated to afford (70 mg, 95%) of(9R,13S)-13-amino-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,hydrochloride as a dark solid. MS(ESI) m/z: 299.08 (M+H)⁺. ¹H NMR (500MHz, CD₃OD) δ 7.81 (s, 1H), 7.77-7.70 (m, 1H), 7.70-7.58 (m, 3H), 4.46(dd, J=12.0, 4.5 Hz, 1H), 4.19-4.07 (m, 3H), 3.45-3.26 (m, 1H),2.75-2.59 (m, 1H), 2.21-2.09 (m, 1H), 1.99-1.86 (m, 2H), 1.58 (td,J=14.3, 8.3 Hz, 1H), 1.29-1.17 (m, 1H), 1.03 (d, J=6.9 Hz, 3H),0.94-0.82 (m, 1H).

48G. Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(23 mg, 86%), a white solid, was prepared in a similar manner as Example1 by using 1-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]prop-2-en-1-oneand13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one.MS(ESI) m/z: 590.3 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.33 (s, 1H),7.58-7.51 (m, 2H), 7.51-7.35 (m, 6H), 7.25 (d, J=7.7 Hz, 1H), 5.72 (s,1H), 5.46 (dd, J=12.8, 3.1 Hz, 1H), 3.97-3.85 (m, 3H), 2.94-2.81 (m,1H), 2.36-2.25 (m, 1H), 2.13-1.98 (m, 2H), 1.98-1.86 (m, 1H), 1.79-1.63(m, 2H), 1.57-1.40 (m, 2H), 1.05 (d, J=6.8 Hz, 3H), 0.93 (t, J=12.7 Hz,1H). Analytical HPLC (Method A) RT=8.52 min, purity=97%; Factor XIaKi=0.13 nM, Plasma Kallikrein Ki=5.5 nM.

Example 49 Preparation of(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(trifluoromethyl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[3-Chloro-2-fluoro-6-(trifluoromethyl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(10.3 mg, 59.1%), a white solid, was prepared in a similar manner asExample 48, using1-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]prop-2-en-1-one and13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one.MS(ESI) m/z: 575.3 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 7.78-7.69 (m, 1H),7.65-7.58 (m, 3H), 7.56-7.51 (m, 2H), 7.46 (d, J=7.7 Hz, 1H), 5.99 (s,1H), 5.68 (dd, J=13.0, 3.1 Hz, 1H), 4.04 (s, 3H), 3.60-3.47 (m, 1H),3.23-3.14 (m, 1H), 2.66-2.39 (m, 3H), 2.33-2.20 (m, 1H), 1.98-1.89 (m,1H), 1.89-1.81 (m, 1H), 1.73-1.66 (m, 1H), 1.66-1.56 (m, 1H), 1.19 (d,J=6.8 Hz, 3H), 1.09 (t, J=12.8 Hz, 1H). Analytical HPLC (Method A)RT=9.56 min, purity=95%; Factor XIa Ki=3.2 nM, Plasma Kallikrein Ki=69nM.

Example 50 Preparation of(9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl})-10,16-difluoro-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

50A. Preparation ofN-[(9S,13S)-10,16-difluoro-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate

Fe₂(C₂O₄)₃.6H₂O (2.16 g, 4.46 mmol) was added to a RBF containing H₂O(30 ml). The suspension was warmed by a water bath (50° C.) to aiddissolution. After 3 h, the clear yellow solution was cooled to 0° C.and purged with Ar. After 20 min, SELECTFLUOR® (1.58 g, 4.46 mmol) inACN (5 ml) was added followed by dropwise addition of tert-butylN-[(9R,10E,13S)-16-fluoro-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,10,14,16-hexaen-13-yl]carbamate(0.370 g, 0.893 mmol) in ACN (10 ml). After 5 min, NaBH₄ (0.270 g, 7.14mmol) was added in two separate portions over a 5 min period. After 15min, the reaction mixture was allowed to come to rt. After 1 h, thereaction mixture was quenched with aq 28-30% NH₄OH (15 mL). After 30min, the reaction mixture was filtered, solids washed with EtOAc,organics washed with brine, dried over Na₂SO₄, filtered, andconcentrated to give a crude mixture of isomers. The material wassubjected chiral purification using CHIRALPAK® IC, 21×250 mm, 5μ, using10% EtOH/90% CO₂ at 45 ml/min, 150 Bar, 40° C. The early eluting isomerwas assigned tert-butylN-[(9S,13S)-10,16-difluoro-3,9-dimethyl-8-oxo-3,4,7triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(99.5% ee; 68 mg, 17.50%) and the second eluting isomer, tert-butylN-[(9R,13S)-11,16-difluoro-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(99.5% ee; 32 mg, 8.3%). 435 (M+H)⁺.

50B. Preparation of(9S,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-10,16-difluoro-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9S,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-10,16-difluoro-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (10 mg, 6%) was prepared by similar methods describedin Example 1 by using Boc-deprotected tert-butylN-[(9R,13S)-11,16-difluoro-3,9-dimethyl-8-oxo-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]carbamate(early eluting isomer) and1-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one,prepared as described for Intermediate 4. The major diastereomer wasisolated by chiral purification using CHIRALPAK® IC, 21×250 mm, 5μ,using 15% MeOH/85% CO₂ at 45 ml/min, 150 Bar, 40° C. and subsequentreverse phase chromatography (PHENOMENEX® Luna Axia C18 5μ 30×100 mmcolumn, 10-minute gradient; Solvent A: 20% MeOH—80% H₂O—0.1% TFA;Solvent B: 90% MeOH—10% H₂O—0.1% TFA). MS(ESI) m/z: 626 (M+H)⁺. ¹H NMR:(400 MHz, DMSO-d₆) δ 9.40 (s, 1H), 8.62-8.56 (m, 1H), 8.12 (d, J=7.5 Hz,1H), 7.75-7.67 (m, 3H), 7.41-7.32 (m, 2H), 7.26 (s, 1H), 6.88 (d, J=9.9Hz, 1H), 6.30-6.23 (m, 1H), 5.97-5.82 (m, 2H), 5.43-5.24 (m, 1H),3.93-3.88 (m, 3H), 3.00 (ddd, J=10.8, 6.9, 4.1 Hz, 1H), 2.34-2.23 (m,1H), 1.89-1.78 (m, 1H), 1.65-1.49 (m, 1H), 1.25-1.10 (m, 1H), 0.81 (d,J=7.0 Hz, 3H), 0.66-0.44 (m, 1H). Analytical HPLC (method X): RT=6.25min, purity=100%; Factor XIa Ki=0.1 nM, Plasma Kallikrein Ki=8 nM.

Example 51 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3-(²H₃)methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

51A. Preparation of(9R,13S)-13-amino-3-(²H₃)methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-Amino-3-(²H₃)methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.28 g, 98%), a gray solid, was prepared in the same manner as(9R,13S)-13-amino-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,described in Example 48F, by substituting1-(²H₃)methyl-4-nitro-1H-pyrazole for 1-methyl-4-nitro-1H-pyrazole.MS(ESI) m/z: 302.5 (M+H)⁺.

51B. Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3-(²H₃)methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3-(²H₃)methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(3 mg, 56.7%) was made in a similar manner as(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,described in Example 48, by substituting(9R,13S)-13-amino-3-(²H₃)methyl-9-methyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onefor(9R,13S)-13-amino-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one.MS(ESI) m/z: 593.5 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.49-8.44 (m, 1H),8.14 (s, 1H), 7.69-7.64 (m, 2H), 7.60-7.56 (m, 2H), 7.56-7.49 (m, 3H),7.38 (d, J=7.7 Hz, 1H), 5.92-5.82 (m, 1H), 5.59 (dd, J=12.7, 3.0 Hz,1H), 3.07-2.94 (m, 1H), 2.51-2.38 (m, 1H), 2.25-2.11 (m, 2H), 2.12-2.00(m, 1H), 1.91-1.78 (m, 2H), 1.72-1.53 (m, 2H), 1.41-1.32 (m, 1H), 1.18(d, J=6.8 Hz, 3H), 1.10-1.00 (m, 1H). Analytical HPLC (Method A) RT=8.17min, purity=90%; Factor XIa Ki=0.18 nM, Plasma Kallikrein Ki=5 nM.

Example 52 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3-(2,2-difluoroethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3-(2,2-difluoroethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onewas prepared according to the procedures described in Example 1 by using1-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one,Intermediate 4, and 1-(2,2-difluoroethyl)-4-nitro-1H-pyrazole,Intermediate 9. ¹H NMR (400 MHz, CD₃CN) δ 8.81 (d, J=5.3 Hz, 1H), 8.47(s, 1H), 7.74 (s, 1H), 7.71-7.63 (m, 4H), 7.62-7.55 (m, 1H), 6.50-6.15(m, 1H), 5.84 (s, 1H), 5.52 (dd, J=12.7, 4.1 Hz, 1H), 4.83-4.71 (m, 2H),3.63-3.49 (m, 2H), 2.64-2.53 (m, 1H), 2.32-2.13 (m, 3H), 1.99-1.84 (m,2H), 1.66-1.52 (m, 1H), 1.41-1.29 (m, 1H), 1.24-1.14 (m, 1H), 1.09 (d,J=6.8 Hz, 3H). MS(ESI) m/z: 641.1 (M+H)⁺. Analytical HPLC (Method A):RT=11.43 min, purity=95%; Factor XIa Ki=0.76 nM, Plasma Kallikrein Ki=22nM.

Example 53 Preparation of(9R)-13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-Chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(6 mg, 9%), as a white solid, was prepared in a manner similar toExample 1 by substituting 1-methyl-4-nitro-1H-pyrazole with1-(difluoromethyl)-4-nitro-1H-pyrazole MS(ESI) m/z: 593.2 (M+H)+. ¹H NMR(400 MHz, CD₃OD) δ 8.93-8.64 (m, 1H), 8.32 (s, 1H), 7.92 (s, 1H), 7.77(s, 2H), 7.72-7.50 (m, 6H), 5.83 (s, 1H), 5.67-5.49 (m, 1H), 4.34-4.08(m, 1H), 3.75-3.62 (m, 1H), 3.60-3.48 (m, 1H), 2.67-2.54 (m, 1H),2.27-2.09 (m, 3H), 1.96 (s, 2H), 1.90-1.76 (m, 1H), 1.67-1.52 (m, 1H),1.50-1.29 (m, 1H), 1.28-1.15 (m, 1H), 1.06 (d, J=7.0 Hz, 3H), 1.01-0.86(m, 1H). Analytical HPLC (Method A): RT=7.19 min, purity=100%; FactorXIa Ki=0.87 nM, Plasma Kallikrein Ki=37 nM.

Example 54 Preparation of(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3-cyclobutyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

85A. Preparation of 1-cyclobutyl-4-nitro-1H-pyrazole

To a dry RBF was added 4-nitro-1H-pyrazole (2 g, 17.69 mmol) and DMF (40mL). The reaction was cooled to 0° C. and NaH (1.415 g, 35.4 mmol) wasadded to the reaction followed by bromocyclobutane (3.58 g, 26.5 mmol).The reaction was slowly warmed to rt and stirred at rt overnight. HPLCshowed the majority still starting material. Then one more eq. of NaHand bromocyclobutane were added and the reaction was stirred at 65° C.for additional 4 h. The reaction was carefully quenched with water (5ml) and the reaction was then partitioned between water (50 ml) andEtOAc (50 ml). The aqueous layer was extracted with EtOAc (2×20 ml). Thecombined EtOAc layer was washed with water (2×40 ml) and brine (40 ml),dried over MgSO₄, filtered and concentrated. The residue was purifiedusing ISCO system (0-50% EtOAc/Hex gradient) to give1-cyclobutyl-4-nitro-1H-pyrazole (640 mg, 3.83 mmol, 21.65% yield) as aclear oil. ¹H NMR (400 MHz, CDCl₃) δ 88.16 (s, 1H), 8.09 (s, 1H), 4.78(quin, J=8.3 Hz, 1H), 2.65-2.39 (m, 4H), 2.04-1.79 (m, 2H). MS(ESI) m/z:167.1 (M+H)⁺.

54B. Preparation of(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3-cyclobutyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-Chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3-cyclobutyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onewas prepared according to the procedures described in Example 1 bysubstituting 1-methyl-4-nitro-1H-pyrazole with1-cyclobutyl-4-nitro-1H-pyrazole. ¹H NMR (400 MHz, CD₃OD) δ 8.59 (d,J=5.1 Hz, 1H), 8.21 (s, 1H), 7.80 (s, 1H), 7.58-7.43 (m, 4H), 7.39 (s,1H), 7.29-7.17 (m, 1H), 5.72 (s, 1H), 5.44 (dd, J=12.5, 3.7 Hz, 1H),4.99 (t, J=8.3 Hz, 1H), 3.45 (br. s., 1H), 3.42-3.30 (m, 1H), 2.74-2.57(m, 2H), 2.51-2.41 (m, 1H), 2.35 (dd, J=7.7, 5.7 Hz, 2H), 2.07-1.93 (m,3H), 1.87-1.75 (m, 3H), 1.73-1.61 (m, 1H), 1.52-1.39 (m, 1H), 1.25-1.17(m, 2H), 1.07 (d, J=5.3 Hz, 1H), 0.94 (d, J=6.8 Hz, 3H). MS(ESI) m/z:597.1 (M+H)⁺. Analytical HPLC (Method B): RT=1.87 min, purity=96%;Factor XIa Ki=7.1 nM, Plasma Kallikrein Ki=150 nM.

Example 55 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3-(difluoromethyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(45 mg, 66%). was prepared in a similar manner to Example 1 bysubstituting 1-methyl-4-nitro-1H-pyrazole with1-(difluoromethyl)-4-nitro-1H-pyrazole and substituting1-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one with1-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl) prop-2-en-1-one.MS(ESI) m/z: 627.3 (M+H). ¹H NMR (500 MHz, CD₃OD) δ 8.77 (d, J=5.2 Hz,1H), 8.47 (s, 1H), 7.78 (s, 1H), 7.73-7.62 (m, 4H), 7.62-7.55 (m, 2H),5.88-5.78 (m, 1H), 5.63-5.50 (m, 1H), 3.76-3.64 (m, 1H), 3.63-3.51 (m,1H), 2.67-2.53 (m, 1H), 2.27 (d, J=6.1 Hz, 2H), 2.24-2.11 (m, 1H),2.02-1.91 (m, 1H), 1.91-1.80 (m, 1H), 1.65-1.53 (m, 1H), 1.40-1.29 (m,1H), 1.28-1.18 (m, 1H), 1.07 (d, J=6.9 Hz, 3H), 1.03-0.86 (m, 1H).Analytical HPLC (Method A): RT=8.36 min, purity=98.8%; Factor XIa Ki=0.1nM, Plasma Kallikrein Ki=6 nM.

Example 56 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3-(2,2-difluorocyclopropyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3-(2,2-difluorocyclopropyl)-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(26 mg, 49%) was prepared in a similar manner to Example 1 by using1-(2,2-difluorocyclopropyl)-4-nitro-1H-pyrazole, Intermediate 15, and1-(5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl) prop-2-en-1-one.MS(ESI) m/z: 653.3 (M+H). ¹H NMR (400 MHz, CD₃CN) δ 8.79 (d, J=5.5 Hz,1H), 8.16 (s, 1H), 7.80 (d, J=8.1 Hz, 2H), 7.77-7.68 (m, 1H), 7.67-7.60(m, 2H), 7.58-7.52 (m, 2H), 5.87 (d, J=9.7 Hz, 1H), 5.40-5.24 (m, 1H),4.63-4.43 (m, 1H), 3.72-3.42 (m, 2H), 2.64-2.50 (m, 1H), 2.44-2.07 (m,5H), 1.31 (br. s., 3H), 1.01 (d, J=6.8 Hz, 3H). Analytical HPLC (MethodA): RT=8.10 min, purity=99%; Factor XIa Ki=0.36 nM, Plasma KallikreinKi=30 nM.

Example 57 Preparation of4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,2,3,6-tetrahydropyridin-4-yl}benzonitrile

(9R,13S)-13-[4-(2-Bromo-5-chlorophenyl)-6-oxo-1,2,3,6-tetrahydropyridin-1-yl]-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate, prepared as Example 37, (0.0094 g, 0.012 mmol),Zn(CN)₂ (0.0007 g, 5.90 μmol), Pd(P(t-Bu)₃)₂ (0.0012 g, 2.36 μmol) inDMF (0.5 mL) was flushed with Ar, sealed and heated at 80° C. for 3days. The reaction mixture was cooled down to rt, filtered andconcentrated. Purification by reverse phase chromatography afforded4-chloro-2-{1-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl]-6-oxo-1,2,3,6-tetrahydropyridin-4-yl}benzonitriletrifluoroacetate (0.0015 g, 17%) as a white solid product. MS(ESI) m/z:515.3 (M+H). ¹H NMR (400 MHz, CD₃OD) δ 8.79 (d, J=5.1 Hz, 1H), 7.88-7.81(m, 1H), 7.75-7.59 (m, 4H), 7.55 (s, 1H), 6.26 (s, 1H), 5.65 (dd,J=12.4, 3.4 Hz, 1H), 4.12-4.08 (m, 3H), 3.88-3.70 (m, 2H), 2.85 (t,J=6.6 Hz, 2H), 2.67-2.56 (m, 1H), 2.32-2.17 (m, 1H), 2.09-1.90 (m, 2H),1.71-1.58 (m, 1H), 1.40-1.21 (m, 2H), 1.12 (d, J=6.8 Hz, 3H) AnalyticalHPLC (Method A): RT=6.41 min, purity=>95%; Factor XIa Ki=4.0 nM, PlasmaKallikrein Ki=14 nM.

Example 58 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (140 mg, 0.174 mmol, 73% yield) was prepared in asimilar way as described in Example 10 by replacing1-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]prop-2-en-1-one with1-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]prop-2-en-1-one,Intermediate 4. ¹H NMR (500 MHz, DMSO-d₆) δ 9.31 (s, 1H), 8.82 (s, 1H),8.60 (d, J=5.2 Hz, 1H), 7.94 (s, 1H), 7.81 (s, 1H), 7.78-7.63 (m, 5H),7.56 (d, J=4.6 Hz, 1H), 7.27-6.99 (m, 1H), 5.71 (s, 1H), 5.48 (d, J=11.3Hz, 1H), 3.54 (br. s., 1H), 3.38 (br. s., 1H), 2.61 (br. s., 1H), 1.72(br. s., 1H), 1.51 (d, J=6.4 Hz, 1H), 1.24 (br. s., 1H), 0.96 (d, J=6.7Hz, 3H), 0.88 (br. s., 1H). MS(ESI) m/z: 577.1 [M+H]⁺. Analytical HPLC(Method B): RT=1.431 min, purity=96.0%; Factor XIa Ki=2.4 nM, PlasmaKallikrein Ki=46 nM.

Example 59 Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-16-fluoro-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

59A. Preparation of(R)—N-[(1E)-(3-bromo-5-fluorophenyl)methylidene]-2-methylpropane-2-sulfinamide

To 3-bromo-5-fluorobenzaldehyde (25 g, 123 mol) dissolved in DCM (200mL) was added (R)-2-methylpropane-2-sulfinamide (14.96 g, 123 mol) andCs₂CO₃ (40.2 g, 123 mol). The reaction mixture was stirred at rtovernight. After this time, the reaction mixture was filtered andconcentrated to give a yellow oil. The yellow oil was purified using a120 g silica gel ISCO column eluted with hexanes and EtOAc to give(R)—N-[(1E)-(3-bromo-5-fluorophenyl)methylidene]-2-methylpropane-2-sulfinamide(35 g, 93%) as a yellow oil. ¹H NMR (500 MHz, DMSO-d₆) δ 8.58-8.55 (m,1H), 8.05-7.98 (m, 1H), 7.84-7.76 (m, 2H), 1.20 (s, 9H). LCMS m/z 306.1(M+H).

59B. Preparation of(R)—N-[(1S)-1-(3-bromo-5-fluorophenyl)but-3-en-1-yl]-2-methylpropane-2-sulfinamide

N-[(1E)-(3-Bromo-5-fluorophenyl)methylidene]-2,2-dimethylpropanamide (35g, 114 mol) was dissolved in THF (500 mL) in a large 3 neck RB flask andflushed with Ar. The solution was cooled to 0° C. and In (18.4 g, 160mol) was added followed by the dropwise addition of allylbromide (15.2g, 126 mol). The reaction was stirred at 0° C. for 2 h, then the icebath was removed and the reaction mixture was stirred at rt overnight.The reaction was quenched with water (2 L) and the gelatinous materialwas filtered through CELITE®. The filtrate was concentrated in vacuo toan oily mass. The crude material was dissolved in water (2 L) and theorganics were extracted with EtOAc (4×200 mL), dried over MgSO₄,filtered and concentrated to give an oil. The oily liquid was purifiedvia a silica gel ISCO column and eluted with DCM/MeOH to afford(R)—N-[(1S)-1-(3-bromo-5-fluorophenyl)but-3-en-1-yl]-2-methylpropane-2-sulfinamide(34.9 g, 88% yield) as a semi solid mass. LCMS m/z 348.2 (M+H). ¹H NMR(500 MHz, DMSO-d₆) δ 7.44-7.38 (m, 2H), 7.26-7.20 (m, 1H), 5.79-5.65 (m,1H), 5.46-5.42 (m, 1H), 5.04-4.98 (m, 2H), 4.41-4.34 (m, 1H), 2.69-2.59(m, 1H), 2.49-2.43 (m, 1H), 1.09 (s, 9H).

59C. Preparation of tert-butylN-[(1S)-1-(3-bromo-5-fluorophenyl)but-3-en-1-yl]carbamate

To a cooled 0° C. solution of(R)—N-[(1S)-1-(3-bromo-5-fluorophenyl)but-3-en-1-yl]-2-methylpropane-2-sulfinamide(21.9 g, 100 mol) dissolved in MeOH (100 mL) was added conc. HCl (50 mL)dropwise and then stirred at 0° C. for 48 h. After this time, thereaction mixture was concentrated to give a white solid mass. Theresidue was dissolved in water (1000 mL) and the organics were extractedwith EtOAc (2×200 mL), dried over MgSO₄, filtered and concentrated to abrown oil (11.5 g). The aqueous layer was basified with 1 N NaOH and theorganics were extracted with EtOAc (2×300 mL), dried over MgSO₄,filtered and concentrated to a brown oil (18 g). The combined oils weredissolved in DCM (500 mL) and to this was added Boc₂O (22 g) followed byTEA (15 mL) and the reaction mixture was stirred at rt overnight. Thereaction mixture was concentrated in vacuo and purified via a 330 gsilica gel Isco column eluting with hexanes and EtOAc to give a whitesolid. The white solid was triturated with hexanes and the precipitatewas collected by filtration to givetert-butyl-N-[(1S)-1-(3-bromo-5-fluorophenyl)but-3-en-1-yl]carbamate(29.5 g, 87% yield).

59D. Preparation of(9R,13S)-13-amino-16-fluoro-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-Amino-16-fluoro-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(19 mg, 92%), a dark solid, was prepared in the same manner as(9R,13S)-13-amino-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,described in Example 48, substitutingtert-butyl-N-[(1S)-1-(3-bromo-5-fluorophenyl)but-3-en-1-yl]carbamate,for tert-butyl-N-[(1S)-1-(3-bromophenyl)but-3-en-1-yl]carbamate. MS(ESI)m/z: 317.4 (M+H)⁺.

59E. Preparation of(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-16-fluoro-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[5-Chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-16-fluoro-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(32 mg, 63.5%), a white solid, was made in a similar manner as(9R,13S)-13-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one, described in Example 48, substituting(9R,13S)-13-amino-16-fluoro-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onefor(9R,13S)-13-amino-3,9-dimethyl-3,4,7-triazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one.MS(ESI) m/z: 608.3 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.46 (s, 1H),7.69-7.63 (m, 2H), 7.62-7.57 (m, 1H), 7.53-7.48 (m, 1H), 7.37 (s, 1H),7.32 (d, J=8.6 Hz, 1H), 7.13 (d, J=9.5 Hz, 1H), 5.87-5.84 (m, 1H), 5.55(dd, J=12.5, 3.1 Hz, 1H), 4.03 (s, 3H), 3.07-3.00 (m, 1H), 2.47-2.40 (m,1H), 2.26-2.06 (m, 3H), 1.88-1.79 (m, 2H), 1.68-1.55 (m, 2H), 1.17 (d,J=6.8 Hz, 3H), 1.09-1.00 (m, 1H). Analytical HPLC (Method A) RT=8.82min, purity=95%; Factor XIa Ki=0.1 nM, Plasma Kallikrein Ki=4 nM.

Example 60 Preparation of(9R,13S)-13-{4-[3-chloro-2-fluoro-6-(trifluoromethyl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3-cyclopropyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-{4-[3-Chloro-2-fluoro-6-(trifluoromethyl)phenyl]-6-oxo-1,2,3,6-tetrahydropyridin-1-yl}-3-cyclopropyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(30 mg, 39%). was prepared in a similar manner to Example 1 bysubstituting 1-methyl-4-nitro-1H-pyrazole with1-cyclopropyl-4-nitro-1H-pyrazole and substituting1-(5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl)prop-2-en-1-one with1-(3-chloro-2-fluoro-6-(trifluoromethyl)phenyl)prop-2-en-1-one. MS(ESI)m/z: 602.4 (M+H). ¹H NMR (400 MHz, CD₃CN) δ 8.79 (d, J=5.7 Hz, 1H), 7.91(br. s., 1H), 7.81 (s, 1H), 7.76 (s, 1H), 7.69 (d, J=7.3 Hz, 1H),7.64-7.58 (m, 1H), 7.43 (s, 1H), 5.95 (s, 1H), 5.54-5.41 (m, 1H),3.90-3.68 (m, 5H), 2.79-2.48 (m, 3H), 2.38-2.21 (m, 1H), 1.66-1.50 (m,1H), 1.30 (br. s., 2H), 1.22-1.08 (m, 4H), 1.04 (d, J=6.8 Hz, 3H).Analytical HPLC (Method A): RT=8.19 min, purity=92%; Factor XIa Ki=7.2nM, Plasma Kallikrein Ki=22 nM.

Example 61 Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyridazin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.02,6]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

61A. Preparation of1-(4-chloro-2-ethenylphenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole

To a cooled (−20° C.) suspension of methyltriphenylphosphonium bromide(1.540 g, 4.31 mmol) in Et₂O (12 mL) was added dropwise a solution of2.5 M nBuLi in hexane (1.58 mL, 3.95 mmol). The resulting yellowsuspension was allowed to warm to 0° C. and stir for 2 h. Then asolution of5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]benzaldehyde (0.99g, 3.59 mmol), prepared as described in Example 40A, in Et₂O (5 mL) wasadded dropwise to give a brown suspension. The suspension was stirred at0° C. for 30 min and then the reaction was allowed to warm to rt. After17 h, the reaction was cooled to 0° C. and then sat NH₄Cl was added. Thereaction was warmed to rt and the layers were separated. The aqueouslayer was extracted with Et₂O. The organic layers were combined andwashed with brine, dried over Na₂SO₄, filtered and concentrated to givea black foam. Purification by normal phase chromatography provided1-(4-chloro-2-ethenylphenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole(0.357 g, 36% yield) as a white solid. MS(ESI) m/z: 274.0 (M+H)+ and276.0 (M+2+H)⁺.

61B. Preparation of4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-5-hydroxy-2,5-dihydrofuran-2-one

To a cooled (−5° C.) clear, colorless solution of Pb(OAc)₄ (0.567 g,1.28 mmol) in TFA (1.3 ml) was added dropwise a clear, colorlesssolution of1-(4-chloro-2-ethenylphenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole(0.350 g, 1.28 mmol) in DCM (1.3 mL). During the addition, the reactiontemperature did not go above 2° C. Following the addition, the resultingclear, pale yellow solution was allowed to warm to rt. After 2h thereaction was cooled to −5° C. and additional Pb(OAc)₄ (0.283 g) in TFA(0.65 mL) was added dropwise. The reaction was allowed to warm to rt.After 2 h, water (10 mL) was added dropwise to give a red-brownsuspension. The suspension was filtered through CELITE®, eluting withDCM. The biphasic filtrate was separated and the aqueous layer wasextracted with DCM. The organic layers were combined and concentrated togive a yellow oil. The oil was dissolved in DCM and washed with water,brine, dried over Na₂SO₄, filtered and concentrated to give2-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}acetaldehyde(0.370 g) as a pale, yellow foam. This material was used in the nextstep without further purification. MS(ESI) m/z: 290.3 (M+H)+ and 292.3(M+2+H)⁺. To a solution of morpholine (0.12 mL, 1.34 mmol) in dioxane(1.7 mL) was added 6 M HCl (0.22 ml, 1.30 mmol) followed by glyoxylicacid monohydrate (0.112 g, 1.21 mmol). Next, a solution of2-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}acetaldehyde(0.370 g, 1.28 mmol) in dioxane (1.7 mL) was added. The reaction mixturewas warmed to reflux. After 5 h, the reaction was stopped and cooled tort. Water and EtOAc were added and the layers were separated. Theaqueous layer was extracted with EtOAc (lx). The organic layers werecombined and washed with brine, dried over Na₂SO₄, filtered andconcentrated to give a golden brown foam. Purification by normal phasechromatography gave4-(3-chloro-2,6-difluorophenyl)-5-hydroxy-2,5-dihydrofuran-2-one (0.112g, 28% yield) as a pale, yellow foam. MS(ESI) m/z: 346.2 (M+H)+ and348.3 (M+2+H)⁺.

61C. Preparation ofN′-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl](tert-butoxy)carbohydrazide

To a cooled (0° C.), purple suspension of(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(0.083 g, 0.277 mmol), prepared as described in Example 1, in DCM (1.848ml) was added dropwise a clear, colorless solution of tert-butyl3-(4-cyanophenyl)-1,2-oxaziridine-2-carboxylate (0.068 g, 0.277 mmol) inDCM (1 mL). Following the addition, the reaction was allowed to warm tort. After 5.5 h, the reaction was stopped and it was concentrated.Purification by normal phase chromatography gaveN′-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl](tert-butoxy)carbohydrazide(0.0310 g, 27% yield) as a white solid. MS(ESI) m/z: 415.5 (M+H)⁺.

61D. Preparation of(9R,13S)-13-hydrazinyl-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,bis-hydrochloride

A suspension ofN′-[(9R,13S)-3,9-dimethyl-8-oxo-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-13-yl](tert-butoxy)carbohydrazide(0.0310 g, 0.075 mmol) in 4 M HCl in dioxane (0.94 ml, 3.74 mmol) wasstirred at rt. MeOH (0.2 mL) was added to give a clear, bright yellowsolution. After 1 h the reaction was concentrated to give a yellowresidue. The residue was dissolved in MeOH and concentrated. This wasrepeated two more times to give(9R,13S)-13-hydrazinyl-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,bis-hydrochloride (0.029 g, 100% yield) as a yellow solid. This materialwas used without further purification. MS(ESI) m/z: 315.5 (M+H)⁺.

61E. Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyridazin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

A slightly cloudy yellow solution of(9R,13S)-13-hydrazinyl-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onebis-hydrochloride (0.029 g, 0.075 mm) and4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-5-hydroxy-2,5-dihydrofuran-2-one(0.026 g, 0.075 mmol) in MeOH (0.75 ml) was heated at 150° C. in amicrowave for 30 min. Upon cooling to rt, DMF (0.75 mL) was added to thereaction mixture. Purification by reverse phase chromatography gave(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyridazin-1-yl)-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (0.0021 g, 3.7% yield), as a white solid. MS(ESI) m/z:624.4 (M+H)⁺ and 626.4 (M+2+H)⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.85 (d,J=0.6 Hz, 1H), 8.62 (d, J=5.2 Hz, 1H), 7.81 (d, J=2.2 Hz, 1H), 7.79-7.76(m, 2H), 7.74-7.70 (m, 1H), 7.58-7.54 (m, 2H), 7.51 (s, 1H), 6.82 (d,J=2.5 Hz, 1H), 6.00 (dd, J=12.1, 4.1 Hz, 1H), 4.05 (s, 3H), 2.63-2.55(m, 1H), 2.48-2.39 (m, 1H), 2.10-2.00 (m, 1H), 2.00-1.91 (m, 1H),1.63-1.55 (m, 1H), 1.36-1.26 (m, 1H), 1.11-1.03 (m, 4H). ¹⁹F NMR (471MHz, CD₃OD) δ −62.65 (s), −77.57 (s). Analytical HPLC (Method A):RT=7.42 min, purity=99.5%. Factor XIa Ki=0.51 nM, Plasma KallikreinKi=66 nM.

Example 62(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-2-oxo-1,2-dihydropyridin-1-yl)-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,trifluoroacetate

A suspension of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,2,3,6-tetrahydropyridin-1-yl)-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(30 mg, 0.048 mmol), prepared as described in Example 42, in DMF (0.5mL) was added K₂CO₃ (66.0 mg, 0.478 mmol), Pearlman's catalyst (6.71 mg,0.048 mmol) and tert-butyl hydroperoxide (70% in water, 0.066 mL, 0.478mmol). After 67 h, the reaction was stopped with the addition of 3 dropsof 10% Na₂S₂O₃. The reaction was purified by reverse phasechromatography which gave(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-2-oxo-1,2-dihydropyridin-1-yl)-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,trifluoroacetate (0.0030 g, 8.4% yield) as a white solid. MS(ESI) m/z:626.4 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.72 (d, J=0.9 Hz, 1H), 8.67 (d,J=5.1 Hz, 1H), 8.01 (d, J=7.0 Hz, 1H), 7.75-7.66 (m, 4H), 7.52-7.48 (m,2H), 6.38 (d, J=2.0 Hz, 1H), 6.10-6.01 (m, 2H), 2.67 (td, J=7.0, 3.2 Hz,1H), 2.27-2.15 (m, 1H), 2.11-2.00 (m, 1H), 1.93 (tt, J=11.6, 5.9 Hz,1H), 1.66-1.53 (m, 1H), 1.47-1.34 (m, 1H), 1.02 (d, J=7.0 Hz, 3H), 0.77(m, 1H). Analytical HPLC (Method A): RT=8.28 min, purity=99.7%. FactorXIa Ki=0.10 nM, Plasma Kallikrein Ki=6 nM.

Example 63(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyridazin-1-yl)-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

63A. Preparation of(9R,13S)-13-hydrazinyl-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,bis-hydrochloride

(9R,13S)-13-Hydrazinyl-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onebis-hydrochloride (0.088 g, 43% over two steps, yellow solid) wasprepared according to the procedures described in Examples 61C and 61D,by replacing(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onewith(9R,13S)-13-amino-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one.MS(ESI) m/z: 318.5 (M+H)⁺.

63B. Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyridazin-1-yl)-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate

(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyridazin-1-yl)-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onetrifluoroacetate (0.0034 g, 4.4% yield) was prepared as described inExample 61E by replacing(9R,13S)-13-hydrazinyl-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onebis-hydrochloride with(9R,13S)-13-hydrazinyl-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,bis-hydrochloride. MS(ESI) m/z: 627.4 (M+H)⁺. ¹H NMR (500 MHz, CD₃OD) δ8.86 (d, J=0.8 Hz, 1H), 8.64 (d, J=5.2 Hz, 1H), 7.82-7.80 (m, 2H), 7.77(dd, J=8.5, 2.5 Hz, 1H), 7.72 (d, J=8.5 Hz, 1H), 7.60-7.58 (m, 1H), 7.57(d, J=2.2 Hz, 1H), 7.51 (s, 1H), 6.83 (d, J=2.2 Hz, 1H), 6.01 (dd,J=12.4, 4.1 Hz, 1H), 2.63-2.55 (m, 1H), 2.48-2.38 (m, 1H), 2.11-2.01 (m,1H), 2.00-1.91 (m, 1H), 1.64-1.55 (m, 1H), 1.36-1.26 (m, 1H), 1.13-1.02(m, 4H). ¹⁹F NMR (471 MHz, CD₃OD) δ −62.46, −77.66. Analytical HPLC(Method A): RT=7.39 min, purity=99.7%. Factor XIa Ki=0.52 nM, PlasmaKallikrein Ki=77 nM.

Example 64(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyridazin-1-yl)-3-(²H₃)methyl-9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

64A. Preparation of(R)—N-[(1E)-(2-bromopyridin-4-yl)methylidene]-2-methylpropane-2-sulfinamide

To a stirred suspension of (R)-2-methylpropane-2-sulfinamide (13.03 g,108 mmol) and Cs₂CO₃ (52.5 g, 161 mmol) in DCM (400 ml) was added2-bromopyridine-4-carbaldehyde (20 g, 108 mmol) over 10 min. Thereaction mixture was then stirred for 18.5 h at rt. The reaction mixturewas concentrated and the residue was diluted with EtOAc (50 ml) andwashed with brine (3×20 ml). The organic layer was dried over MgSO₄ andfiltered and then the filtrate was concentrated. The residue waspurified by normal phase chromatography using hexanes and EtOAc aseluents to afford (27.2 g, 87%) of(R)—N-[(1E)-(2-bromopyridin-4-yl)methylidene]-2-methylpropane-2-sulfinamideas a white solid. MS(ESI) m/z: 289-291.0 (M+H)⁺.

64B. Preparation of(R)—N-[(1S)-1-(2-bromopyridin-4-yl)but-3-en-1-yl]-2-methylpropane-2-sulfonamide

To a solution of(R)—N-[(1E)-(2-bromopyridin-4-yl)methylidene]-2-methylpropane-2-sulfinamide(0.73 g, 2.52 mmol) and indium (0.435 g, 3.79 mmol) in THF (6 ml) wasslowly added 3-bromoprop-1-ene (0.458 g, 3.79 mmol) and resultingsolution was heated at 60° C. for 18 h. The reaction mixture was cooled,filtered through CELITE® and the filtrate was concentrated. To theresidue was added EtOAc (100 ml) and 5% NaHCO₃ (aq) (1000 ml) and anemulsion formed immediately. The suspension was filtered through paper.The organic layer was washed with brine, dried over Na₂SO₄ filtered, andconcentrated. The resulting residue was purified by normal phasechromatography using hexanes and EtOAc as eluents to afford (0.62 g,74%) of(R)—N-[(1S)-1-(2-bromopyridin-4-yl)but-3-en-1-yl]-2-methylpropane-2-sulfonamideas a yellow liquid. MS(ESI) m/z: 331-333.0 (M+H)⁺.

64C. Preparation of tert-butylN-[(1S)-1-(2-bromopyridin-4-yl)but-3-en-1-yl]carbamate

To a solution of(R)—N-[(1S)-1-(2-bromopyridin-4-yl)but-3-en-1-yl]-2-methylpropane-2-sulfinamide(1.38 g, 4.17 mmol) in MeOH (10 ml) was added 4N HCl in dioxane (5.21mL, 20.83 mmol). The reaction mixture was stirred for 1.5 h at rt, thenwas concentrated. To the resulting residue was added ACN (10 ml), TEA(5.81 ml, 41.7 mmol) and Boc₂O (1.818 g, 8.33 mmol). After 18 h, thereaction mixture was concentrated and the residue was taken up in EtOAc,washed with water, brine, dried over MgSO₄, filtered and concentrated.The resulting residue was purified by normal phase chromatography usinghexanes and EtOAc as eluents to afford (0.80 g, 58.7%) of tert-butylN-[(1S)-1-(2-bromopyridin-4-yl)but-3-en-1-yl]carbamate as a pale yellowoil. MS(ESI) m/z: 324-326.1 (M+H)⁺.

64D. Preparation of(9R,13S)-13-amino-3-(²H₃)methyl-9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-Amino-3-(²H₃)methyl-9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onewas prepared in a similar manner as(9R,13S)-13-amino-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,as described in Example 17B through 17G, replacing(S)-tert-butyl(1-(4-chloropyridin-2-yl)but-3-en-1-yl)carbamate, with(S)-tert-butyl(1-(2-bromopyridin-4-yl)but-3-en-1-yl)carbamate. MS(ESI)m/z: 303.3 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.70 (d, J=5.3 Hz, 1H),7.58 (s, 1H), 7.50-7.42 (m, 2H), 4.14-4.05 (m, 1H), 2.72 (td, J=6.7, 3.5Hz, 1H), 2.06-1.94 (m, 2H), 1.65-1.50 (m, 2H), 1.41-1.26 (m, 1H), 1.02(d, J=6.8 Hz, 3H), 0.70-0.53 (m, 1H).

64E. Preparation of(9R,13S)-13-hydrazinyl-3-(²H₃)methyl-9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,bis-hydrochloride

(9R,13S)-13-Hydrazinyl-3-(²H₃)methyl-9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,bis-hydrochloride (0.067 g, 35% over two steps, yellow solid) wasprepared according to the procedures described in Examples 61C and 61D,by replacing(9R,13S)-13-amino-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-onewith (9R,13S)-13-amino-3-(²H₃)methyl-9-methyl-3,4,7,17tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one.MS(ESI) m/z: 318.5 (M+H)⁺.

64F. Preparation of(9R,13S)-13-(4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-6-oxo-1,6-dihydropyridazin-1-yl)-3-(²H₃)methyl-9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one

(9R,13S)-13-(4-{5-Chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]pheny}-6-oxo-1,6-dihydropyridazin-1-yl)-3-(²H₃)methyl-9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one(2.7 mg, 2.7%) was prepared in a similar manner as Example 61E, byreplacing (9R,13S)-13-hydrazinyl-3-(²H₃)methyl-9-methyl-3,4,7,15-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,bis-hydrochloride as described in Example 61D with(9R,13S)-13-hydrazinyl-3-(²H₃)methyl-9-methyl-3,4,7,17-tetraazatricyclo[12.3.1.0^(2,6)]octadeca-1(18),2(6),4,14,16-pentaen-8-one,bis-hydrochloride. MS(ESI) m/z: 627.4 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD) δ8.90 (d, J=0.7 Hz, 1H), 8.70-8.64 (m, 1H), 7.91-7.75 (m, 4H), 7.64-7.58(m, 1H), 7.53-7.48 (m, 1H), 7.21 (dd, J=5.3, 1.5 Hz, 1H), 6.90 (d, J=2.4Hz, 1H), 6.10 (dd, J=12.1, 4.2 Hz, 1H), 2.67 (dt, J=6.9, 3.6 Hz, 1H),2.57-2.45 (m, 1H), 2.09-1.97 (m, 2H), 1.64 (dd, J=14.1, 5.7 Hz, 1H),1.42-1.32 (m, 1H), 1.25-1.19 (m, 1H), 1.10 (d, J=7.0 Hz, 3H), containsminor diastereomer. Analytical HPLC (Method A): RT=8.32 min, purity=95%.Factor XIa Ki=0.71 nM, Plasma Kallikrein Ki=52.6 nM.

What is claimed is:
 1. A compound of Formula (Ia):

or a stereoisomer, a tautomer, a pharmaceutically acceptable saltthereof, wherein: --- is an optional bond; ring A is independentlyselected from

R¹ is independently selected from H, F, OH, and C₁₋₄ alkyl; R² isindependently selected from H, F, and OH; R³ is independently selectedfrom H, C₁₋₄alkyl, C₁₋₄haloalkyl, —(CH₂)_(n)—OR⁵, —(CH₂)_(n)—C(O)OR⁵,C₃₋₆ cycloalkyl optionally substituted with halogen, and 5- to6-membered heteroaryl comprising carbon atoms and 1-2 nitrogen atoms andoptionally substituted with R¹; provided only one R³ group is present onthe ring; R⁴ is independently selected from H, OH, F, OC₁₋₄ alkyl, C₁₋₄alkyl, and CN; R⁵ is independently selected from H and C₁₋₄ alkyl; R⁶ isindependently selected from H, F, Cl, Br, CN, OCH₃, CH₃, C(O)CH₃, CHF₂,CCH₃F₂, CF₃, OCHF₂, NHC(O)C₁₋₄ alkyl, C₃₋₆ cycloalkyl, and 5-memberedheterocycle substituted with R⁹; R⁷ is independently selected from H andF; R⁸ is independently selected from H, F, Cl, and OCH₃; R⁹ isindependently selected from H, cyano, C₁₋₄ alkyl, haloalkyl, andhalogen; and n, at each occurrence, is an integer selected from 1 and 2.2. The compound of claim 1 having Formula (IIa):

or a stereoisomer, a tautomer, a pharmaceutically acceptable saltthereof, wherein: ring A is independently selected from

R¹ is independently selected from H and C₁₋₃alkyl; R² is independentlyselected from H and F; R³ is independently selected from H, C₁₋₃alkyl,C₁₋₃haloalkyl, —(CH₂)_(n)—OR⁵, —(CH₂)_(n)—C(O)OR⁵, and C₃₋₄ cycloalkyloptionally substituted with halogen; R⁴ is independently selected from Hand F; R⁵ is independently selected from H and C₁₋₄ alkyl; R⁶ isindependently selected from H, F, Cl, Br, CN, CF₃, C(O)CH₃, CHF₂,CCH₃F₂, CF₃, OCHF₂,

R⁷ is independently selected from H and F; R⁸ is independently selectedfrom H, F, Cl, and OCH₃; R⁹ is independently selected from H, CHF₂, andCF₃; R^(9′) is independently selected from H, F, Cl, CN, CHF₂, and CF₃;and n, at each occurrence, is an integer selected from 1 and
 2. 3. Thecompound of claim 2, or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt thereof, wherein: R¹ is independently selected from H,CH₃, and CH(CH₃)₂; R² is independently selected from H and F; R³ isindependently selected from H, CH₃, CD₃, CH₂CH₃, —CHF₂, —CH₂CHF₂,—CH₂CF₃, —CH₂CH₂OH, CH₂CH₂OC(CH₃)₃, —CH₂C(O)OH, cyclopropyl optionallysubstituted with F, and cyclobutyl; R⁶ is independently selected from H,F, Cl, Br, CN, CF₃, C(O)CH₃, CHF₂, CCH₃F₂, CF₃, OCHF₂,

R⁷ is independently selected from H and F; R⁸ is independently selectedfrom H, F, Cl, and OCH₃; R⁹ is independently selected from H, CHF₂, andCF₃; and R^(9′) is independently selected from H, F, Cl, CN, CHF₂, andCF₃.
 4. The compound of claim 1 having Formula (IIIa):

or a stereoisomer, a tautomer, a pharmaceutically acceptable saltthereof, wherein: ring A is independently selected from

R¹ is independently selected from H, CH₃, and CH(CH₃)₂; R² isindependently selected from H and F; R³ is independently selected fromH, CH₂C(═O)OH, CH₂C(═O)OCH₂CH₃,

R⁴ is independently selected from H and F; R⁶ is independently selectedfrom H, F, Cl, Br, CN, CF₃, C(O)CH₃, CHF₂, CCH₃F₂, CF₃, OCHF₂,

R⁷ is independently selected from H and F; R⁸ is independently selectedfrom H, F, Cl, and OCH₃; R⁹ is independently selected from H, CHF₂, andCF₃; and R^(9′) is independently selected from H, F, Cl, CN, CHF₂, andCF₃.
 5. The compound of claim 1, or a stereoisomer, a tautomer, apharmaceutically acceptable salt thereof, wherein: R³ is independentlyselected from H, CH₃, CD₃, CH₂CH₃, —CHF₂, —CH₂CHF₂, —CH₂CF₃, —CH₂CH₂OH,CH₂CH₂OC(CH₃)₃, —CH₂C(O)OH, CH₂C(═O)OH, CH₂C(═O)OCH₂CH₃, cyclopropyloptionally substituted with F, and cyclobutyl,

R⁶ is independently selected from H, F, Cl, Br, CN, CF₃, C(O)CH₃, CHF₂,CCH₃F₂, CF₃, OCHF₂,

R⁷ is independently selected from H and F; R⁸ is Cl; R⁹ is independentlyselected from H, CHF₂, and CF₃; and R^(9′) is independently selectedfrom H, F, Cl, CN, CHF₂, and CF₃;
 6. A compound having Formula (IV):

or a stereoisomer, a tautomer, a pharmaceutically acceptable saltthereof, wherein: ring A is independently selected from

R¹ is independently selected from H and C₁₋₃alkyl; R² is independentlyselected from H and F; R³ is independently selected from H, CD₃, CHF₂,and CH₃; R⁴ is independently selected from H and halogen; R⁷ isindependently selected from H and F; R⁸ is independently selected fromH, F, Cl, and OCH₃; and R⁹ is independently selected from H, F, Cl, CN,and CF₃.
 7. A compound having Formula (V):

or a stereoisomer, a tautomer, a pharmaceutically acceptable saltthereof, wherein: ring A is independently selected from

R¹ is independently selected from H and C₁₋₃alkyl; R² is independentlyselected from H and F; R³ is independently selected from H, CD₃, CHF₂,and CH₃; R⁴ is independently selected from H and halogen; R⁶ isindependently selected from H, F, Cl, Br, CN, CF₃, C(O)CH₃, CHF₂,CCH₃F₂, CF₃, OCHF₂,

R⁷ is independently selected from H and F; R⁸ is independently selectedfrom H, F, Cl, and OCH₃; R⁹ is independently selected from H, CHF₂, andCF₃; and R^(9′) is independently selected from H, F, Cl, CN, CHF₂, andCF₃.
 8. A compound of claim 1 selected from

or a stereoisomer, a tautomer, a pharmaceutically acceptable saltthereof.
 9. A pharmaceutical composition comprising one or morecompounds according to claim 1 and a pharmaceutically acceptable carrieror diluent.
 10. A method for the treatment and/or prophylaxis of athromboembolic disorder, comprising: administering to a patient in needthereof a therapeutically effective amount of a compound of claim 1, ora stereoisomer, a tautomer, or a pharmaceutically acceptable saltthereof, wherein the thromboembolic disorder is selected from arterialcardiovascular thromboembolic disorders, venous cardiovascularthromboembolic disorders, and thromboembolic disorders in the chambersof the heart or in the peripheral circulation.
 11. A method according toclaim 10, wherein the thromboembolic disorder is selected from unstableangina, an acute coronary syndrome, atrial fibrillation, myocardialinfarction, transient ischemic attack, stroke, atherosclerosis,peripheral occlusive arterial disease, venous thrombosis, deep veinthrombosis, thrombophlebitis, arterial embolism, coronary arterialthrombosis, cerebral arterial thrombosis, cerebral embolism, kidneyembolism, pulmonary embolism, and thrombosis resulting from medicalimplants, devices, or procedures in which blood is exposed to anartificial surface that promotes thrombosis.